Polyarylcarboxamides useful as lipid lowering agents

ABSTRACT

Polyarylcarboxamide compounds of formula (I)  
                 
are useful as lipid lowering agents.

The present invention is concerned with novel polyarylcarboxamideshaving apolipoprotein B inhibiting activity and concomitant lipidlowering activity. The invention further relates to methods forpreparing such compounds, pharmaceutical compositions comprising saidcompounds as well as the use of said compounds as a medicine for thetreatment of hyperlipidemia, obesity and type II diabetes.

BACKGROUND OF THE INVENTION

Obesity is the cause of a myriad of serious health problems like theadult onset of diabetes and heart disease. In addition, the loss ofweight is getting an obsession among an increasing proportion of thehuman population.

The causal relationship between hypercholesterolemia, particularly thatassociated with increased plasma concentrations of low densitylipoproteins (hereinafter referred as LDL) and very low densitylipoproteins (hereinafter referred as VLDL), and prematureatherosclerosis and/or cardiovascular disease is now widely recognized.However, a limited number of drugs are presently available for thetreatment of hyperlipidemia. Drugs primarily used for the management ofhyperlipidemia include bile acid sequestrant resins such ascholestyramine and colestipol, fibric acid derivatives such asbezafibrate, clofibrate, fenofibrate, ciprofibrate and gemfibrozil,nicotinic acid and cholesterol synthesis inhibitors such as HMGCo-enzyme-A reductase inhibitors. The inconvenience of administration (agranular form to be dispersed in water or orange juice) and the majorside-effects (gastrointestinal discomfort and constipation) of bile acidsequestrant resins constitute major drawbacks. Fibric acid derivativesinduce a moderate decrease (by 5 to 25%) of LDL cholesterol (except inhypertriglyceridemic patients in whom initially low levels tend toincrease) and, although usually well tolerated, suffer from side-effectsincluding potentiation of warfarine, pruritus, fatigue, headache,insomnia, painful reversible myopathy and stiffness in large musclegroups, impotency and impaired renal function. Nicotinic acid is apotent lipid lowering agent resulting in a 15 to 40% decrease in LDLcholesterol (and even 45 to 60% when combined with a bile acidsequestrant resin) but with a high incidence of troublesome side-effectsrelated to the drug's associated vasodilatory action, such as headache,flushing, palpitations, tachychardia and occasional syncopes, as well asother side-effects such as gastro-intestinal discomfort, hyperucemia andimpairment of glucose tolerance. Among the family of HMG Co-enzyme-Areductase inhibitors, lovastatin and simvastatin are both inactiveprodrugs containing a lactone ring which is hydrolyzed in the liver toform the corresponding active hydroxy-acid derivative. Inducing areduction of LDL cholesterol by 35 to 45%, they are generally welltolerated with alow incidence of minor side effects. However there stillremains a need for new lipid lowering agents with improved efficiencyand/or acting via other mechanisms than the above mentioned drugs.

Plasma lipoproteins are water-soluble complexes of high molecular weightformed from lipids (cholesterol, triglyceride, phospholipids) andapolipoproteins. Five major classes of lipoproteins that differ in theproportion of lipids and the type of apolipoprotein, all having theirorigin in the liver and/or the intestine, have been defined according totheir density (as measured by ultracentrifugation). They include LDL,VLDL, intermediate density lipoproteins (hereinafter referred as IDL),high density lipoproteins (hereinafter referred as HDL) andchylomicrons. Ten major human plasma apolipoproteins have beenidentified. VLDL, which is secreted by the liver and containsapolipoprotein B (hereinafter referred as Apo-B), undergoes degradationto LDL which transports 60 to 70% of the total serum cholesterol. Apo-Bis also the main protein component of LDL. Increased LDL-cholesterol inserum, due to oversynthesis or decreased metabolism, is causally relatedto atherosclerosis. In contrast high density lipoproteins (hereinafterreferred as HDL), which contain apolipoprotein A1, have a protectiveeffect and are inversely correlated with the risk of a coronary heartdisease. The HDL/LDL ratio is thus a convenient method of assessing theatherogenic potential of an individual's plasma lipid profile.

The two isoforms of apolipoprotein (apo) B, apo B-48 and apo B-100, areimportant proteins in human lipoprotein metabolism. Apo B-48, so namedbecause it appears to be about 48% the size of apo B-100 on sodiumdodecyl sulfate-polyacrylamide gels, is synthesized by the intestine inhumans. Apo B-48 is necessary for the assembly of chylomicrons andtherefore has an obligatory role in the intestinal absorption of dietaryfats. Apo B-100, which is produced in the liver in humans, is requiredfor the synthesis and secretion of VLDL. LDL, which contain about ⅔ ofthe cholesterol in human plasma, are metabolic products of VLDL. ApoB-100 is virtually the only protein component of LDL. Elevatedconcentrations of apo B-100 and LDL cholesterol in plasma are recognizedrisk factors for developing atherosclerotic coronary artery disease.

A large number of genetic and acquired diseases can result inhyperlipidemia. They can be classified into primary and secondaryhyperlipidemic states. The most common causes of the secondaryhyperlipidemias are diabetes mellitus, alcohol abuse, drugs,hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasisand bulimia. Primary hyperlipidemias have also been classified intocommon hypercholesterolaemia, familial combined hyperlipidaemia,familial hypercholesterolaemia, remnant hyperlipidaemia,chylomicronaemia syndrome and familial hypertriglyceridaemia.

Microsomal triglyceride transfer protein (hereinafter referred as MTP)is known to catalyze the transport of triglyceride and cholesteryl esterby preference to phospholipids such as phosphatidylcholine. It wasdemonstrated by D. Sharp et al., Nature (1993) 365:65 that the defectcausing abetalipoproteinemia is in the MTP gene. This indicates that MTPis required for the synthesis of Apo B-containing lipoproteins such asVLDL, the precursor to LDL. It therefore follows that an MTP inhibitorwould inhibit the synthesis of VLDL and LDL, thereby lowering levels ofVLDL, LDL, cholesterol and triglyceride in humans. MTP inhibitors havebeen reported in Canadian patent application No. 2,091,102 and in WO96/26205. MTP inhibitors belonging to the class of polyarylcarboxamideshave also been reported in U.S. Pat. No. 5,760,246 as well as inWO-96/40640 and WO-98/27979.

One of the goals of the present invention is to provide an improvedtreatment for patients suffering from obesity or atherosclerosis,especially coronary atherosclerosis and more generally from disorderswhich are related to atherosclerosis, such as ischaemic heart disease,peripheral vascular disease and cerebral vascular disease. Another goalof the present invention is to cause regression of atherosclerosis andinhibit its clinical consequences, particularly morbidity and mortality.

SUMMARY OF THE INVENTION

The present invention is based on the unexpected discovery that a classof novel polyarylcarboxamide compounds is acting as selective MTPinhibitors, i.e. is able to selectively block MTP at the level of thegut wall in mammals, and is therefore a promising candidate as amedicine, namely for the treatment of hyperlipidemia. The presentinvention additionally provides several methods for preparing suchpolyarylcarboxamide compounds, as well as pharmaceutical compositionsincluding such compounds. Furthermore, the invention provides a certainnumber of novel compounds which are useful intermediates for thepreparation of the therapeutically active polyarylcarboxamide compounds,as well as methods for preparing such intermediates. Finally, theinvention provides a method of treatment of a condition selected fromatherosclerosis, pancreatitis, obesity, hypercholesterolemia,hypertriglyceridemia, hyperlipidemia, diabetes and type II diabetes,comprising administering a therapeutically active polyarylcarboxamidecompound to a mammal.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a family of novel polyarylcarboxamidecompounds of formula (I)

the N-oxides, the pharmaceutically acceptable addition salts and thestereochemically isomeric forms thereof, wherein

-   -   Z₁ is selected from (CH₂)_(n) wherein n is 1 to 3, CH₂CH₂O and        OCH₂CH₂;    -   Z₂ is (CH₂)_(m) wherein m is 1 or 2;    -   X₁ represents O, CH₂, CO, NH, CH₂O, OCH₂, CH₂S, SCH₂ or a direct        bond;    -   X₂ and X₃ are each independently selected from CH, N and a sp²        carbon atom;    -   R₁ is hydrogen or C₁₋₄alkyl;    -   Ar¹ is an aromatic ring selected from phenyl, naphthalenyl,        pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,        triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,        oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted        with one or two R₃ substituents;    -   Ar² is an aromatic ring selected from phenyl, naphthalenyl,        pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,        triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,        oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted        with one, two or three R₄ substituents;    -   each R₂ and R₃ is independently selected from C₁₋₄alkyl,        C₁₋₄alkyloxy, halo, trifluoromethyl;    -   each R₄ is independently selected from C₁₋₄alkyl, C₁₋₄alkyloxy,        halo, hydroxy, mercapto, cyano, nitro, C₁₋₄alkylthio or        polyhaloC₁₋₆alkyl, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;    -   p¹ and p² are each 0 to 2;    -   p³ is 0 to 3;    -   X₁ and R₄ taken together with the aromatic rings Ar¹ and Ar² to        which they are attached may form a fluoren-1-yl or a        fluoren-4-yl group;    -   A represents a C₁₋₆alkanediyl substituted with one or two groups        selected from aryl, heteroaryl and C₃₋₁₀cycloalkyl; or when X₃        is CH, A may also represent a nitrogen atom substituted with        hydrogen, C₁₋₁₀alkyl, aryl, heteroaryl, arylC₁₋₁₀alkyl,        heteroarylC₁₋₁₀alkyl or C₃₋₁₀ cycloalkyl;    -   B represents hydrogen; C₁₋₁₀alkyl; aryl or heteroaryl each        optionally substituted with a group selected from halo, cyano,        nitro, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino,        di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkylaminocarbonyl and        di(C₁₋₁₀alkyl)aminocarbonyl; arylC₁₋₁₀alkyl; heteroaryl        C₁₋₁₀alkyl; C₃₋₁₀cycloalkyl; polyhaloC₁₋₆alkyl; C₃₋₆alkenyl;        C₃₋₆alkynyl; NR₆R₇; or OR₈;    -   R₆ and R₇ each independently represent hydrogen, C₁₋₁₀alkyl,        aryl or heteroaryl each optionally substituted with a group        selected from halo, cyano, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino,        di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,        C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl;        arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl, C₃₋₁₀cycloalkyl,        C₇₋₁₀polycycloalkyl, polyhaloC₁₋₆alkyl, C₃₋₈alkenyl,        C₃₋₈alkynyl, fused benzo-C₅₋₈cycloalkyl, and wherein R₆ and R₇        taken together with the nitrogen atom to which they are attached        may form a C₄₋₈ saturated heterocyclic radical; and    -   R₈ represents C₁₋₁₀alkyl, aryl or heteroaryl each optionally        substituted with a group selected from halo, cyano, nitro,        C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino,        C₁₋₁₀acyl, C₁₋₁₀alkylthio, C₁₋₁₀alkylaminocarbonyl and        di(C₁₋₁₀alkyl)aminocarbonyl; arylC₁₋₁₀alkyl;        heteroarylC₁₋₁₀alkyl; C₃₋₁₀cycloalkyl; C₇₋₁₀ polycycloalkyl;        polyhaloC₁₋₆alkyl; C₃₋₈alkenyl; C₃₋₈alkynyl; or fused        benzo-C₅₋₈cycloalkyl.        Unless otherwise stated, as used in the foregoing definitions        and hereinafter:    -   halo is generic to fluoro, chloro, bromo and iodo;    -   C₁₋₄alkyl defines straight and branched chain saturated        hydrocarbon radicals having from 1 to 4 carbon atoms such as,        for example, methyl, ethyl, propyl, n-butyl, 1-methylethyl,        2-methylpropyl, 1,1-dimethylethyl and the like;    -   C₁₋₆alkyl is meant to include C₁₋₄alkyl (as hereinabove defined)        and the higher homologues thereof having 5 or 6 carbon atoms,        such as for instance 2-methylbutyl, n-pentyl, dimethylpropyl,        n-hexyl, 2-methylpentyl, 3-methylpentyl and the like;    -   C₁₋₁₀alkyl is meant to include C₁₋₆alkyl (as hereinabove        defined) and the higher homologues thereof having 7 to 10 carbon        atoms, such as for instance heptyl, ethylhexyl, octyl, nonyl,        decyl and the like;    -   C₃₋₁₀cycloalkyl is generic to cyclopropyl, cyclobutyl,        cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and        cyclodecyl;    -   polyhaloC₁₋₆alkyl is defined as polyhalosubstituted C₁₋₆alkyl,        in particular C₁₋₆alkyl (as hereinabove defined) substituted        with 2 to 13 halogen atoms such as difluoromethyl,        trifluoromethyl, trifluoroethyl, octafluoropentyl and the like;    -   aryl is defined as mono- and polyaromatic groups such as phenyl        or naphthalenyl optionally substituted with one to three        substituents each independently selected from nitro, azido,        cyano, halo, hydroxy, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₄alkyloxy,        polyhaloC₁₋₆alkyl, amino, mono- or di(C₁₋₆alkyl)amino;    -   heteroaryl is defined as mono- and polyheteroaromatic groups        such as those including one or more heteroatoms selected from        nitrogen, oxygen, sulfur and phosphorus, in particular        pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,        triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,        oxazolyl, pyrrolyl, furanyl, thienyl and the like, including all        possible isomeric forms thereof;    -   C₃₋₆alkenyl defines straight and branched chain hydrocarbon        radicals containing one double bond and having from 3 to 6        carbon atoms such as, for example, 2-propenyl, 3-butenyl,        2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl,        3-hexenyl, 2-hexenyl and the like;    -   C₃₋₆alkynyl defines straight and branched chain hydrocarbon        radicals containing one triple bond and having from 3 to 6        carbon atoms such as, for example, 2-propynyl, 3-butynyl,        2-butynyl, 2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl,        3-hexynyl, 2-hexynyl and the like;    -   C₄₋₈cycloalkenyl defines cyclic hydrocarbon radicals containing        one double bond and having from 4 to 8 carbon atoms such as, for        example cyclobutenyl, cyclopentenyl, cyclohexenyl,        cycloheptenyl, cyclooctenyl and the like;    -   fused benzo-C₅₋₈cycloalkyl defines radicals such as, for        instance, indanyl, 1,2,3,4-tetrahydronaphthalenyl, fluorenyl and        the like;    -   C₇₋₁₀polycycloalkyl defines radicals having from 7 to 10 carbon        atoms such as, for instance, norbornyl;    -   C₁₋₆alkylamino defines primary amino radicals having from 1 to 6        carbon atoms such as, for example, methylamino, ethylamino,        propylamino, iso propylamino, butylamino, isobutylamino and the        like;    -   di(C₁₋₆alkyl)amino defines secondary amino radicals having from        1 to 6 carbon atoms such as, for example, dimethylamino,        diethylamino, dipropylamino, di-isopropylamino,        N-methyl-N′-ethylamino, N-ethyl-N′-propylamino and the like;    -   C₁₋₆alkylthio defines a C₁₋₆alkyl group attached to a sulfur        atom, such as methylthio, ethylthio, propylthio, isopropylthio,        butylthio and the like;    -   C₁₋₆acyl defines a C₁₋₆alkyl group attached to a carbonyl group        such as, for instance acetyl, propionyl, butyryl, isobutyryl and        the like.

The pharmaceutically acceptable addition salts as mentioned hereinaboveare meant to include the therapeutically active non-toxic acid additionsalt forms which the compounds of formula (I) are able to form and whichmay conveniently be obtained by treating the base form of such compoundswith an appropriate acid. Examples of such appropriate acids include,for instance, inorganic acids such as hydrohalic acids, e.g.hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, lactic,pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioicacid), maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic (i.e. 2-hydroxybenzoic), p-aminosalicylic, pamoic and thelike. Conversely the salt form can be converted by treatment with anappropriate alkali into the free base form.

The term pharmaceutically acceptable addition salt as used hereinabovealso includes the solvates which the compounds of formula (I) as well astheir salts are able to form, such as for example hydrates, alcoholatesand the like.

The N-oxide forms of the compounds of formula (I), are meant to includethose compounds wherein one or more nitrogen atoms are oxidized, usingmethods well known in the art for converting a trivalent nitrogen intoits N-oxide form. Said N-oxidation reaction may usually be carried outby reacting the compound of formula (I) with3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic orinorganic peroxide in at least one suitable solvent. Appropriateinorganic peroxides include for example hydrogen peroxide and alkalimetal or alkaline-earth metal peroxides, e.g. sodium or potassiumperoxides. Appropriate organic peroxides may comprise peroxy acids suchas, for example benzenecarboperoxoic acid or halo substitutedbenzenecarboperoxoic acid (e.g. 3-chlorobenzene-carboperoxoic acid),peroxoalkanoic acids (e.g. peroxoacetic acid) and alkylhydroperoxides(e.g. tert-butyl hydroperoxide). Suitable solvents for this reactioninclude for instance water, lower alcohols (e.g. ethanol and the like),hydrocarbons (e.g. toluene), ketones (e.g. 2-butanone), halogenatedhydrocarbons (e.g. dichloromethane) and mixtures of such solvents.

The polyarylcarboxamide compounds of formula (I) may have at least onechiral center in the A group and/or the B group and/or the cyclic groupincluding X₂ and X₃.

The term “stereochemically isomeric forms” as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise stated, the chemical designation of compoundsdenotes the mixture of all possible stereochemically isomeric forms,said mixtures containing all diastereomers and enantiomers of the basicmolecular structure. More particularly, stereogenic centers may haveeither the R— or S-configuration; substituents on bivalent cyclicsaturated radicals may have either the cis- or trans-configuration. Thesame definition applies to the various novel intermediates, as describedherein, which are used to prepare the polyarylcarboxamide compounds offormula (I).

Pure stereoisomeric forms of the said compounds and intermediates aredefined as isomers substantially free of other enantiomeric ordiastereomeric forms of the same basic molecular structure. Inparticular, the term “stereoisomerically pure” or “chirally pure”relates to compounds or intermediates having a stereoisomeric excess ofat least 80% (i.e. at least 90% of one isomer and at most 10% of theother possible isomers), preferably at least 90%, more preferably atleast 94% and most preferably at least 97%. The terms “enantiomericallypure” and “diastereomerically pure” should be understood in a similarway, having regard to the enantiomeric excess, respectively thediastereomeric excess, of the mixture in question.

Consequently, if a mixture of enantiomers is obtained during any of thefollowing preparation methods, it can be separated by liquidchromatography using a suitable chiral stationary phase. Suitable chiralstationary phases are, for example, polysaccharides, in particularcellulose or amylose derivatives. Commercially available polysaccharidebased chiral stationary phases are ChiralCel™ CA, OA, OB, OC, OD, OF,OG, OJ and OK, and Chiralpak™ AD, AS, OP(+) and OT(+). Appropriateeluents or mobile phases for use in combination with said polysaccharidechiral stationary phases are hexane and the like, modified with analcohol such as ethanol, isopropanol and the like.

The terms cis and trans are used herein in accordance with ChemicalAbstracts nomenclature and refer to the position of the substituents ona ring moiety.

The absolute stereochemical configuration of the polyarylcarboxamidecompounds of formula (I) and of the intermediates used in theirpreparation may easily be determined by those skilled in the art whileusing well-known methods such as, for example, X-ray diffraction.

Furthermore, some polyarylcarboxamide compounds of formula (I) and someof the intermediates used in their preparation may exhibit polymorphism.It is to be understood that the present invention encompasses anypolymorphic forms possessing properties useful in the treatment of theconditions noted hereinabove.

A group of interesting compounds consists of those compounds of formula(I) wherein one or more of the following restrictions apply:

-   a) R¹ is hydrogen;-   b) R² is hydrogen or C₁₋₄alkyl;-   c) R³ is hydrogen or C₁₋₄alkyl;-   d) R⁴ is hydrogen, C₁₋₄alkyl or trifluoromethyl;-   e) p¹ is 1;-   f) p² is 1;-   g) p³ is 1;-   h) the bivalent radical A is C₁₋₆alkanediyl substituted with one    aryl group, in particular A is a methylene group substituted with    phenyl;-   i) B is C₁₋₄alkyloxy, or C₁₋₁₀alkylamino.

Interesting compounds are those compounds of formula (I) wherein Z₁, Z₂,X₂ and X₃ taken together form a six-membered heterocycle.

Particular compounds are those compounds of formula (I) wherein radicalB represents methyloxy or ethyloxy.

Other particular compounds are those compounds of formula (I) wherein R₂and/or R₃ are/is C₁₋₄alkyl.

Yet other particular compounds are those compounds of formula (I)wherein R₄ is C₁₋₄alkyl or trifluoromethoxy.

More preferred compounds are those particular compounds of formula (I)wherein Z₁, Z₂, X₂ and X₃ taken together form a piperidine or piperazinegroup and X₁ is a direct bond.

More preferred compounds of formula (I) are those compounds wherein R₂and R₃ are each hydrogen and R₄ is hydrogen, trifluoromethyl, chloro ortert-butyl.

Most preferred compound of formula (I) are

and the stereoisomeric forms, the pharmaceutically acceptable acidaddition salts, or the N-oxides thereof.

One advantage of the present invention is the easiness with which thecompounds of formula (I) can be manufactured by a high number ofdifferent processes. Some of these processes will now be described indetails, without pretending to provide an exhaustive list of the methodsfor preparing the said compounds.

A first process for preparing a polyarylcarboxamide compound accordingto this invention is a process wherein an intermediate phenylene aminehaving the formula

wherein Z₁, Z₂, X₂, X₃, p¹, R₁, R₂, A and B are as defined in formula(I), is reacted with a polyarylcarboxylic acid or halide having theformula (III),

wherein X₁, Ar¹, Ar², p², p³, R₃ and R₄ are as defined in formula (I)and Y₁ is selected from hydroxy and halo, in at least one reaction-inertsolvent and optionally in the presence of a suitable base, the saidprocess further optionally comprising converting a compound of formula(I) into an addition salt thereof, and/or preparing stereochemicallyisomeric forms thereof. In case Y₁ is hydroxy, it may be convenient toactivate the biphenylcarboxylic acid of formula (III) by adding aneffective amount of a reaction promoter. Non-limiting examples of suchreaction promoters include carbonyldiimidazole, diimides such asN,N′-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and functionalderivatives thereof. For this type of acylation procedure, it ispreferred to use a polar aprotic solvent such as, for instance,methylene chloride. Suitable bases for carrying out this first processinclude tertiary amines such as triethylamine, triisopropylamine and thelike. Suitable temperatures for carrying out the first process of theinvention typically range from about 20° C. to about 140° C., dependingon the particular solvent used, and will most often be the boilingtemperature of the said solvent.

A second process for preparing a polyarylcarboxamide compound accordingto this invention, wherein X₃ is nitrogen, is a process wherein anintermediate having the formula

wherein Z₁, Z₂, X₁, X₂, p¹, p², p³, Ar¹, Ar², R₁, R₂, R₃ and R₄ re asdefined in formula (I) and X₃ is nitrogen, is reacted with a reactanthaving the formula (V)

wherein A and B are as defined in formula (I) and Y₂ is selected fromhalo, tosyloxy, mesyloxy, naphtylsulfonyloxy, or -A-Y₂ is R′₅COR₅,wherein R₅ and R′₅ are such that the radical R′₅CHR₅ is encompassed bythe definition of A in formula (I), in at least one reaction-inertsolvent and optionally in the presence of at least one suitablenucleophilic substitution activator and/or a suitable base, the saidprocess further optionally comprising converting a compound of formula(I) into an addition salt thereof, and/or preparing stereochemicallyisomeric forms thereof. When Y₂ is halo, the alkylation couplingprocedure may for instance be effected in the presence of sodium orpotassium carbonate or a tertiary amine such as triethylamine ordiisopropylethylamine in a solvent such as dimethylformamide ormethylisopropylketone and optionally in the presence of a catalyticamount of potassium iodide in order to enhance nucleophilicsubstitution. Intermediates of formula (IV) wherein X₃ is nitrogen mayalso be reductively N-alkylated by means of an aldehyde or a ketone offormula (V) wherein -A-Y₂ is R′₅COR₅, thus forming compounds of formula(I). Said reductive N-alkylation may be performed in a reaction-inertsolvent such as for example toluene, methanol, tetrahydrofuran or amixture thereof, and in the presence of a reducing agent. Non-limitingexamples of such reducing agents include hydrogen and borohydrides, e.g.sodium borohydride, zinc borohydride, lithium borohydride, sodiumcyanoborohydride, triacetoxy borohydride and the like. When aborohydride is used as the reducing agent, it may be convenient toperform the N-alkylation in the additional presence of a catalyst.Non-limiting examples of such catalysts include transition metalalkoxides, e.g. titanium(IV)isopropoxide, titanium(IV)-n-butoxide andthe like, as disclosed in J. Org. Chem. (1990), 55:2552-4. When hydrogenis used as the reducing agent, it may be convenient to perform theN-alkylation in the additional presence of a catalyst. Non-limitingexamples of catalysts suitable for this purpose include a noble metalsupported on a carrier such as for instance palladium-on-charcoal orplatinum-on-charcoal. The formation of a Schiff base in a first step ofthe said reductive N-alkylation reaction may be further enhanced by theadditional presence of a suitable reagent such as aluminium terbutoxide,calcium oxide, calcium hydride and the like. An appropriatecatalyst-poison, e.g. thiophene, butanethiol, quinoline sulfur or thelike, may also be added to the reaction mixture in order to preventundesired hydrogenation of certain functional groups in the reactantsand/or the reaction product. Stirring and optionally elevatedtemperature and/or pressure may further enhance the rate of such areaction.

A third process for preparing a polyarylcarboxamide compound of theinvention is a process wherein an intermediate having the formula

wherein Z₁, Z₂, X₁, X₂, X₃, p¹, p², p³, Ar¹, Ar², R₁, R₂, R₃, R₄ and Aare as defined in formula (I) and Y₃ is selected from halo and hydroxy,is reacted with a reactant of the formula BH, wherein B is NR₆R₇ or OR₈and R₆, R₇ and R₈ are as defined in formula (I), in at least onereaction-inert solvent and optionally in the presence of at least onesuitable coupling reagent and/or a suitable base, the said processfurther optionally comprising converting a compound of formula (I) intoan addition salt thereof, and/or preparing stereochemically isomericforms thereof. In case Y₃ is hydroxy, it may be convenient to activatethe carboxylic acid of formula (VI) by adding an effective amount of areaction promoter. Non-limiting examples of such reaction promotersinclude carbonyldiimidazole, diimides such asN,N′-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbo-diimide, and functionalderivatives thereof. In case a chirally pure reactant of formula (V) isused, a fast and enantiomerization-free reaction of the intermediate offormula (VI) with the said reactant may be performed in the furtherpresence of an effective amount of a compound such ashydroxybenzotriazole, benzotriazolyloxytris (dimethylamino)phosphoniumhexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate,bromotripyrrolidinophosphonium hexafluorophosphate, or a functionalderivative thereof, such as disclosed by D. Hudson, J. Org. Chem.(1988), 53:617. In case Y₃ is hydroxy and B is OR₈, then theesterification reaction may conveniently be performed in the presence ofan effective amount of an acid such as sulfuric acid and the like.

A fourth process for preparing a polyarylcarboxamide compound accordingto this invention wherein X₃ is nitrogen and wherein A is a groupsuitable for a Michael addition reaction, is a process wherein anintermediate having the formula (IV), wherein X₃ is nitrogen, is reactedwith a reactant of the formula (VII)

wherein B is as defined in formula (I), and Y₄ and Y′₄ are such that theradical

is encompassed by the definition of A in formula (I), in at least onereaction-inert solvent, the said process further optionally comprisingconverting a compound of formula (I) into an addition salt thereof,and/or preparing stereochemically isomeric forms thereof. Thereaction-inert solvent may be, for instance, dimethylformamide ormethanol and the reaction temperature may be the boiling point of thesaid solvent. Contrary to most of the alternative processes forpreparing the polyarylcarboxamide compounds of this invention, thisfourth process does not require the presence of a catalyst or otherwisecoupling reagent in order to quantatively yield the target compound. Abase such as sodium carbonate, potassium carbonate, cesium carbonate andthe like may optionally be added to the reaction mixture. Asconventionally defined in the art, A preferably is an α,β-unsaturatedcarbonyl compound, such as a ketone or an ester, the β carbon atom ofwhich is susceptible of a nucleophilic attack. Non-limiting examples ofgroups A suitable for such a Michael addition reaction include forinstance:

A fifth process for preparing a polyarylcarboxamide compound accordingto this invention is a process wherein an intermediate having theformula (VIII)

wherein X₁, p¹, p², p³, Ar¹, Ar², R₁, R₂, R₃ and R₄ are as defined informula (I) and Y₅ is selected from halo, B(OH)₂, alkylboronates andcyclic analogues thereof, is reacted with a reactant having the formula(IX)

wherein Z₁, Z₂, X₃, A and B are as defined in formula (I), in at leastone reaction-inert solvent and optionally in the presence of at leastone transition metal coupling reagent and/or at least one suitableligand, the said process further optionally comprising converting acompound of formula (I) into an addition salt thereof, and/or preparingstereochemically isomeric forms thereof. This type of reaction beingknown in the art as the Buchwaldt reaction, reference to the applicablemetal coupling reagents and/or suitable ligands, e.g. palladiumcompounds such as palladium tetra(triphenylphosphine),tris(dibenzylidene-acetone dipalladium,2,2′-bis(diphenylphosphino)-1,1′-binaphtyl and the like, may be foundfor instance in Tetrahedron Letters (1996) 37(40) 7181-7184 and J. Am.Chem. Soc. (1996) 118:7216. If Y₅ is B(OH)₂, an alkylboronate or acyclic analogue thereof, then cupric acetate should be used as thecoupling reagent, according to Tetrahedron Letters (1998) 39:2933-6.

A sixth process for preparing a polyarylcarboxamide compound accordingto this invention is a process wherein an intermediate having theformula (X)

wherein p¹, p², p³, Ar¹, Ar², X₁, R₁, R₂, R₃ and R₄ are as defined informula (I), is reacted with a reactant having the formula (XI)

wherein Z₁, Z₂, X₃, A and B are as defined in formula (I), one of Y₆ andY₇ is selected from bromo, iodo and trifluoromethylsulfonate and theother of Y₆ and Y₇ is selected from tri(C₁₋₄alkyl) tin, B(OH)₂,alkylboronates and cyclic analogues thereof, in at least onereaction-inert solvent and optionally in the presence of at least onetransition metal coupling reagent and/or at least one suitable ligandsuch as palladium associated with triphenylphosphine, triphenylarsineand the like, the said process further optionally comprising convertinga compound of formula (I) into an addition salt thereof, and/orpreparing stereochemically isomeric forms thereof. This type of reactionbeing known in the art as the Stille reaction or the Suzuki reaction,reference to the applicable transition metal coupling reagents and/orsuitable ligands may be found for instance in Syn. Letters(1998)6,671-5, in Chem. Rev. (1999)99(6)1549-1581 and in The StilleReaction (John Wiley & Sons, Inc.) ISBN 0-471-31273-8.

A seventh process for preparing a polyarylcarboxamide compound accordingto this invention is a process wherein an intermediate having theformula (XII)

wherein Z₁, Z₂, X₂, X₃, p¹, p², Ar¹, R₁, R₂, R₃, A and B are as definedin formula (I) and Y₈ is selected from bromo, iodo andtrifluoromethylsulfonate, is reacted either with an aryl-boric acidhaving the formula (XIII a)

wherein p³, Ar² and R₄ are as defined in formula (I), or with anaryl-tin reactant having the formula (XIII b)

wherein R₃, R₄, Ar² and p³ are as defined in formula (I), in at leastone reaction-inert solvent and optionally in the presence of at leastone transition metal coupling reagent and/or at least one suitableligand, the said process further optionally comprising converting acompound of formula (I) into an addition salt thereof, and/or preparingor stereochemically isomeric forms thereof. This type of reaction beingknown in the art as the Stille reaction or the Suzuki reaction,reference to the applicable transition metal coupling reagents and/orsuitable ligands may be found for instance in the literature citedabove. Exemplary coupling reagents for this process are e.g.bis(triphenylphospine) dichloropalladium and diacetylpalladium.Exemplary reaction-inert solvents for this reaction are 1,4-dioxane,toluene, dimethylformamide, tetrahydrofuran, dimethylether and the like.

Furthermore, a process for preparing a polyarylcarboxamide compound ofthe formula (I) wherein B is NR₆R₇, from a polyarylcarboxamide compoundof the formula (I) wherein B is OR₅ is a process comprising in a firststep hydrolyzing the latter and in a second step reacting the resultingcorresponding carboxylic acid with an amine having the formula HNR₆R₇ inat least one reaction-inert solvent and further optionally comprisingconverting the resulting compound of formula (I) wherein B is NR₆R₇ intoan addition salt thereof, and/or preparing stereochemically isomericforms thereof. The hydrolysis first step is preferably effected in anacidic medium such as strongly concentrated hydrochloric acid andoptionally in the presence of an organic solvent such as dioxane.

The compounds of formula (I) can also conveniently be prepared usingsolid phase synthesis techniques. In general, solid phase synthesisinvolves reacting an intermediate in a synthesis with a polymer support.This polymer supported intermediate can then be carried on through anumber of synthetic steps. After each step, impurities are removed byfiltering the resin and washing it numerous times with various solvents.At each step the resin can be split up to react with variousintermediates in the next step thus allowing for the synthesis of alarge number of compounds. After the last step in the procedure theresin is treated with a reagent or process to cleave the resin from thesample. More detailed explanation of the techniques used in solid phasechemistry are described in for example “The Combinatorial Index” (B.Bunin, Academic Press) and Novabiochem's 1999 Catalogue & PeptideSynthesis Handbook (Novabiochem AG, Switzerland) both incorporatedherein by reference.

Furthermore, the invention provides compounds of any of the formulae(II), (III), (IV), (VI), (VIII), (X) and (XII) hereunder:

wherein

-   -   Z₁ is selected from (CH₂)_(n) wherein n is 1 to 3, CH₂CH₂O and        OCH₂CH₂;    -   Z₂ is (CH₂)_(m) wherein m is 1 or 2;    -   X₁ represents O, CH₂, CO, NH, CH₂O, OCH₂, CH₂S, SCH₂ or a direct        bond;    -   X₂ and X₃ are each independently selected from CH, N and a sp2        carbon atom;    -   R₁ is hydrogen or C₁₋₄alkyl;    -   Ar¹ is an aromatic ring selected from phenyl, naphthalenyl,        pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,        triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,        oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted        with one or two R₃ substituents;    -   Ar² is an aromatic ring selected from phenyl, naphthalenyl,        pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,        triazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,        oxazolyl, pyrrolyl, furanyl and thienyl, optionally substituted        with one, two or three R₄ substituents;    -   each R₂ and R₃ is independently selected from C₁₋₄alkyl,        C₁₋₄alkyloxy, halo and trifluoromethyl;    -   each R₄ is independently selected from C₁₋₄alkyl, C₁₋₄alkyloxy,        halo, hydroxy, mercapto, cyano, nitro, C₁₋₄alkylthio or        polyhaloC₁₋₆alkyl, amino, C₁₋₄alkylamino and di(C₁₋₄alkyl)amino;    -   p¹ and p² are each 0 to 2;    -   p³ is 0 to 3;    -   X₁ and R₄ taken together with the aromatic rings to which they        are attached may form a fluoren-1-yl or a fluoren-4-yl group;    -   A represents a C₁₋₆ alkanediyl optionally substituted with one        or two groups selected from aryl, heteroaryl and C₃₋₁₀        cycloalkyl; oxygen; or a direct bond;    -   B represents hydrogen; C₁₋₁₀alkyl; aryl or heteroaryl each        optionally substituted with a group selected from halo, cyano,        nitro, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino,        di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,        C₁₋₁₀alkoxycarbonyl, C₁₋₁₀alkylaminocarbonyl and        di(C₁₋₁₀alkyl)aminocarbonyl; arylC₁₋₁₀alkyl;        heteroarylC₁₋₁₀alkyl; C₃₋₁₀cycloalkyl; polyhaloC₁₋₆alkyl;        C₃₋₆alkenyl; C₃₋₆alkynyl; NR₆R₇; or OR₈;    -   R₆ and R₇ each independently represent hydrogen, C₁₋₁₀alkyl,        aryl or heteroaryl each optionally substituted with a group        selected from halo, cyano, C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino,        di(C₁₋₁₀alkyl)amino, C₁₋₁₀acyl, C₁₋₁₀alkylthio,        C₁₋₁₀alkylaminocarbonyl and di(C₁₋₁₀alkyl)aminocarbonyl;        arylC₁₋₁₀alkyl, heteroarylC₁₋₁₀alkyl, C₃₋₁₀cycloalkyl,        C₇₋₁₀polycycloalkyl, polyhaloC₁₋₆alkyl, C₃₋₈alkenyl,        C₃₋₈alkynyl, fused benzo-C₅₋₈cycloalkyl, and wherein R₆ and R₇        taken together with the nitrogen atom to which they are attached        may form a C₄₋₈ saturated heterocyclic radical;    -   R₈ represents C₁₋₁₀alkyl, aryl or heteroaryl each optionally        substituted with a group selected from halo, cyano, nitro,        C₁₋₄alkyloxy, amino, C₁₋₁₀alkylamino, di(C₁₋₁₀alkyl)amino,        C₁₋₁₀acyl, C₁₋₁₀alkylthio, C₁₋₁₀alkylaminocarbonyl and        di(C₁₋₁₀alkyl)aminocarbonyl; arylC₁₋₁₀alkyl;        heteroarylC₁₋₁₀alkyl; C₃₋₁₀cycloalkyl; C₇₋₁₀polycycloalkyl;        polyhaloC₁₋₆alkyl; C₃₋₈alkenyl; C₃₋₈alkynyl; or fused benzo-C₅₋₈        cycloalkyl;    -   when X₃ is CH, A may also represent a nitrogen atom substituted        with hydrogen, C₁₋₁₀alkyl, aryl, heteroaryl, arylC₁₋₁₀alkyl,        heteroarylC₁₋₁₀alkyl or C₃₋₁₀cycloalkyl;    -   Y₁ and Y₃ are each independently selected from hydroxy and halo;    -   Y₅ is selected from halo, B(OH)₂, alkylboronates and cyclic        analogues thereof; and    -   Y₆ and Y₈ are each independently selected from bromo, iodo and        trifluoromethylsulfonate,        which are useful as intermediates for the preparation of the        polyarylcarboxamide compounds of the present invention. In turn,        the present invention provides methods for preparing the        above-mentioned families of intermediate compounds, such as        disclosed in the foregoing examples.

The polyarylcarboxamide compounds of formula (I), the N-oxide forms, thepharmaceutically acceptable salts and stereoisomeric forms thereofpossess favourable apolipoprotein B inhibiting activity and concomitantlipid lowering activity. Therefore the present compounds are useful as amedicine especially in a method of treating patients suffering fromhyperlipidemia, obesity, atherosclerosis or type II diabetes. Inparticular the present compounds may be used for the manufacture of amedicine for treating disorders caused by an excess of very low densitylipoproteins (VLDL) or low density lipoproteins (LDL), and especiallydisorders caused by the cholesterol associated with said VLDL and LDL.

The causal relationship between hypercholesterolemia—particularly thatassociated with increased plasma concentrations of low densitylipoproteins (LDL) and very low density lipoproteins (VLDL)—andpremature atherosclerosis and cardiovascular disease is wellestablished. VLDL is secreted by the liver and contains apolipoprotein B(apo-B); these particles undergo degradation in the circulation to LDL,which transports about 60 to 70% of the total serum cholesterol. Apo-Bis also the principal protein component of LDL. IncreasedLDL-cholesterol in serum, due to oversynthesis or decreased metabolism,is causally related to atherosclerosis. In contrast, high densitylipoproteins (HDL) which contain apolipoprotein A1, have a protectiveeffect and are inversely correlated with risk of coronary heart disease.The HDL/LDL ratio is thus a convenient method of assessing theatherogenic potential of an individual's plasma lipid profile.

The principal mechanism of action of the compounds of formula (I)appears to involve inhibition of MTP (microsomial triglyceride transferprotein) activity in hepatocytes and intestinal epithelial cells,resulting in decreased VLDL and chylomicron production, respectively.This is a novel and innovative approach to hyperlipidemia, and isexpected to lower LDL-cholesterol and triglycerides through reducedhepatic production of VLDL and intestinal production of chylomicrons.

A large number of genetic and acquired diseases can result inhyperlipidemia. They can be classified into primary and secondaryhyperlipidemic states. The most common causes of the secondaryhyperlipidemias are diabetes mellitus, alcohol abuse, drugs,hypothyroidism, chronic renal failure, nephrotic syndrome, cholestasisand bulimia. Primary hyperlipidemias are common hypercholesterolaemia,familial combined hyperlipidaemia, familial hypercholesterolaemia,remnant hyperlipidaemia, chylomicronaemia syndrome, familialhypertriglyceridaemia. The present compounds may also be used to preventor treat patients suffering from obesitas or from atherosclerosis,especially coronary atherosclerosis and more in general disorders whichare related to atherosclerosis, such as ischaemic heart disease,peripheral vascular disease, cerebral vascular disease. The presentcompounds may cause regression of atherosclerosis and inhibit theclinical consequences of atherosclerosis, particularly morbidity andmortality.

In view of the utility of the compounds of formula (I), it follows thatthe present invention also provides a method of treating warm-bloodedanimals, including humans, (generally called herein patients) sufferingfrom disorders caused by an excess of very low density lipoproteins(VLDL) or low density lipoproteins (LDL), and especially disorderscaused by the cholesterol associated with said VLDL and LDL.Consequently a method of treatment is provided for relieving patientssuffering from conditions, such as, for example, hyperlipidemia,obesity, atherosclerosis or type II diabetes.

Apo B-48, synthetized by the intestine, is necessary for the assembly ofchylomicrons and therefore has an obligatory role in the intestinalabsorption of dietary fats. The present invention providespolyarylcarboxamide compounds which are acting as selective MTPinhibitors at the level of the gut wall.

Additionally the present invention provides pharmaceutical compositionscomprising at least one pharmaceutically acceptable carrier and atherapeutically effective amount of a polyarylcarboxamide compoundhaving the formula (I).

In order to prepare the pharmaceutical compositions of this invention,an effective amount of the particular compound, in base or addition saltform, as the active ingredient is combined in intimate admixture with atleast one pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for oral administration,rectal administration, percutaneous administration or parenteralinjection.

For example in preparing the compositions in oral dosage form, any ofthe usual liquid pharmaceutical carriers may be employed, such as forinstance water, glycols, oils, alcohols and the like in the case of oralliquid preparations such as suspensions, syrups, elixirs and solutions;or solid pharmaceutical carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets. Because of their easyadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. For parenteral injection compositions, thepharmaceutical carrier will mainly comprise sterile water, althoughother ingredients may be included in order to improve solubility of theactive ingredient. Injectable solutions may be prepared for instance byusing a pharmaceutical carrier comprising a saline solution, a glucosesolution or a mixture of both. Injectable suspensions may also beprepared by using appropriate liquid carriers, suspending agents and thelike. In compositions suitable for percutaneous administration, thepharmaceutical carrier may optionally comprise a penetration enhancingagent and/or a suitable wetting agent, optionally combined with minorproportions of suitable additives which do not cause a significantdeleterious effect to the skin. Said additives may be selected in orderto facilitate administration of the active ingredient to the skin and/orbe helpful for preparing the desired compositions. These topicalcompositions may be administered in various ways, e.g., as a transdermalpatch, a spot-on or an ointment. Addition salts of the compounds offormula (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the pharmaceuticalcompositions of the invention in dosage unit form for ease ofadministration and uniformity of dosage. “Dosage unit form” as usedherein refers to physically discrete units suitable as unitary dosages,each unit containing a predetermined amount of active ingredientcalculated to produce the desired therapeutic effect in association withthe required pharmaceutical carrier. Examples of such dosage unit formsare tablets (including scored or coated tablets), capsules, pills,powder packets, wafers, injectable solutions or suspensions,teaspoonfuls, tablespoonfuls and the like, and segregated multiplesthereof.

For oral administration, the pharmaceutical compositions of the presentinvention may take the form of solid dose forms, for example, tablets(both swallowable and chewable forms), capsules or gelcaps, prepared byconventional means with pharmaceutically acceptable excipients andcarriers such as binding agents (e.g. pregelatinised maize starch,polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like),fillers (e.g. lactose, microcrystalline cellulose, calcium phosphate andthe like), lubricants (e.g. magnesium stearate, talc, silica and thelike), disintegrating agents (e.g. potato starch, sodium starchglycollate and the like), wetting agents (e.g. sodium laurylsulphate)and the like. Such tablets may also be coated by methods well known inthe art.

Liquid preparations for oral administration may take the form of e.g.solutions, syrups or suspensions, or they may be formulated as a dryproduct for admixture with water and/or another suitable liquid carrierbefore use. Such liquid preparations may be prepared by conventionalmeans, optionally with other pharmaceutically acceptable additives suchas suspending agents (e.g. sorbitol syrup, methylcellulose,hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifyingagents (e.g. lecithin or acacia), non-aqueous carriers (e.g. almond oil,oily esters or ethyl alcohol), sweeteners, flavours, masking agents andpreservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

Pharmaceutically acceptable sweeteners useful in the pharmaceuticalcompositions of the invention comprise preferably at least one intensesweetener such as aspartame, acesulfame potassium, sodium cyclamate,alitame, a dihydrochalcone sweetener, monellin, stevioside sucralose(4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose) or, preferably,saccharin, sodium or calcium saccharin, and optionally at least one bulksweetener such as sorbitol, mannitol, fructose, sucrose, maltose,isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.Intense sweeteners are conveniently used in low concentrations. Forexample, in the case of sodium saccharin, the said concentration mayrange from about 0.04% to 0.1% (weight/volume) of the final formulation.The bulk sweetener can effectively be used in larger concentrationsranging from about 10% to about 35%, preferably from about 10% to 15%(weight/volume).

The pharmaceutically acceptable flavours which can mask the bittertasting ingredients in the low-dosage formulations are preferably fruitflavours such as cherry, raspberry, black currant or strawberry flavour.A combination of two flavours may yield very good results. In thehigh-dosage formulations, stronger pharmaceutically acceptable flavoursmay be required such as Caramel Chocolate, Mint Cool, Fantasy and thelike. Each flavour may be present in the final composition in aconcentration ranging from about 0.05% to 1% (weight/volume).Combinations of said strong flavours are advantageously used. Preferablya flavour is used that does not undergo any change or loss of tasteand/or color under the circumstances of the formulation.

The polyarylcarboxamide compounds of this invention may be formulatedfor parenteral administration by injection, conveniently intravenous,intramuscular or subcutaneous injection, for example by bolus injectionor continuous intravenous infusion. Formulations for injection may bepresented in unit dosage form, e.g. in ampoules or multi-dosecontainers, including an added preservative. They may take such forms assuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulating agents such as isotonizing, suspending, stabilizingand/or dispersing agents. Alternatively, the active ingredient may bepresent in powder form for mixing with a suitable vehicle, e.g. sterilepyrogen-free water, before use.

The polyarylcarboxamide compounds of this invention may also beformulated in rectal compositions such as suppositories or retentionenemas, e.g. containing conventional suppository bases such as cocoabutter and/or other glycerides.

The polyarylcarboxamide compounds of this invention may be used inconjunction with other pharmaceutical agents, in particular thepharmaceutical compositions of the present invention may furthercomprise at least one additional lipid-lowering agent, thus leading to aso-called combination lipid-lowering therapy. The said additionallipid-lowering agent may be, for instance, a known drug conventionallyused for the management of hyperlipidaemia such as e.g. a bile acidsequestrant resin, a fibric acid derivative or nicotinic acid aspreviously mentioned in the background of the invention. Suitableadditional lipid-lowering agents also include other cholesterolbiosynthesis inhibitors and cholesterol absorption inhibitors,especially HMG-CoA reductase inhibitors and HMG-CoA synthase inhibitors,HMG-CoA reductase gene expression inhibitors, CETP inhibitors, ACATinhibitors, squalene synthetase inhibitors and the like.

Any HMG-CoA reductase inhibitor may be used as the second compound inthe combination therapy aspect of this invention. The term “HMG-CoAreductase inhibitor” as used herein, unless otherwise stated, refers toa compound which inhibits the biotransformation ofhydroxymethylglutaryl-coenzyme A to mevalonic acid as catalyzed by theenzyme HMG-CoA reductase. Such inhibition may be determined readily byone skilled in the art according to standard assays, i.e. Methods ofEnzymology (1981) 71:455-509. Exemplary compounds are described e.g. inU.S. Pat. No. 4,231,938 (including lovastatin), U.S. Pat. No. 4,444,784(including simvastatin), U.S. Pat. No. 4,739,073 (includingfluvastatin), U.S. Pat. No. 4,346,227 (including pravastatin),EP-A-491,226 (including rivastatin) and U.S. Pat. No. 4,647,576(including atorvastatin).

Any HMG-CoA synthase inhibitor may be used as the second compound in thecombination therapy aspect of this invention. The term “HMG-CoA synthaseinhibitor” as used herein, unless otherwise stated, refers to a compoundwhich inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A fromacetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzymeHMG-CoA synthase. Such inhibition may be determined readily by oneskilled in the art according to standard assays, i.e. Methods ofEnzymology (1985) 110:19-26. Exemplary compounds are described e.g. inU.S. Pat. No. 5,120,729 relating to beta-lactam derivatives, U.S. Pat.No. 5,064,856 relating to spiro-lactone derivatives and U.S. Pat. No.4,847,271 relating to oxetane compounds.

Any HMG-CoA reductase gene expression inhibitor may be used as thesecond compound in the combination therapy aspect of this invention.These agents may be HMG-CoA reductase trancription inhibitors that blockthe transcription of DNA or translation inhibitors that preventtranslation of mRNA coding for HMG-CoA reductase into protein. Suchinhibitors may either affect trancription or translation directly or maybe biotransformed into compounds having the above-mentioned attributesby one or more enzymes in the cholesterol biosynthetic cascade or maylead to accumulation of a metabolite having the above-mentionedactivities. Such regulation may be determined readily by one skilled inthe art according to standard assays, i.e. Methods of Enzymology (1985)110:9-19. Exemplary compounds are described e.g. in U.S. Pat. No.5,041,432 and E. I. Mercer, Prog. Lip. Res. (1993) 32:357-416.

Any CETP inhibitor may be used as the second compound in the combinationtherapy aspect of this invention. The term “CETP inhibitor” as usedherein, unless otherwise stated, refers to a compound which inhibits thecholesteryl ester transfer protein (CETP) mediated transport of variouscholesteryl esters and triglycerides from HDL to LDL and VLDL. Exemplarycompounds are described e.g. in U.S. Pat. No. 5,512,548, in J. Antibiot.(1996) 49(8):815-816 and Bioorg. Med. Chem. Lett. (1996) 6:1951-1954.

Any ACAT inhibitor may be used as the second compound in the combinationtherapy aspect of this invention. The term “ACAT inhibitor” as usedherein, unless otherwise stated, refers to a compound which inhibits theintracellular esterification of dietary cholesterol by the enzyme acylCoA:cholesterol acyltransferase. Such inhibition may be determinedreadily by one skilled in the art according to standard assays, i.e. themethod of Heider et al., Journal of Lipid Research (1983) 24:1127.Exemplary compounds are described e.g. in U.S. Pat. No. 5,510,379, in WO96/26948 and WO 96/10559.

Any squalene synthetase inhibitor may be used as the second compound inthe combination therapy aspect of this invention. The term “squalenesynthetase inhibitor” as used herein, unless otherwise stated, refers toa compound which inhibits the condensation of two molecules offarnesylpyrophosphate to form squalene, catalyzed by the enzyme squalenesynthetase. Such inhibition may be determined readily by one skilled inthe art according to standard methods, i.e. Methods of Enzymology (1985)110:359-373. Exemplary compounds are described e.g. in EP-A-567,026, inEP-A-645,378 and in EP-A-645,377.

Those of skill in the treatment of hyperlipidemia will easily determinethe therapeutically effective amount of a polyarylcarboxamide compoundof this invention from the test results presented hereinafter. Ingeneral it is contemplated that a therapeutically effective dose will befrom about 0.001 mg/kg to about 5 mg/kg of body weight, more preferablyfrom about 0.01 mg/kg to about 0.5 mg/kg of body weight of the patientto be treated. It may be appropriate to administer the therapeuticallyeffective dose in the form of two or more sub-doses at appropriateintervals throughout the day. Said sub-doses may be formulated as unitdosage forms, for example each containing from about 0.1 mg to about 350mg, more particularly from about 1 to about 200 mg, of the activeingredient per unit dosage form.

The exact dosage and frequency of administration depends on theparticular polyarylcarboxamide compound of formula (I) used, theparticular condition being treated, the severity of the condition beingtreated, the age, weight and general physical condition of theparticular patient as well as the other medication (including theabove-mentioned additional lipid-lowering agents), the patient may betaking, as is well known to those skilled in the art. Furthermore, saideffective daily amount may be lowered or increased depending on theresponse of the treated patient and/or depending on the evaluation ofthe physician prescribing the polyarylcarboxamide compounds of theinstant invention. The effective daily amount ranges mentionedhereinabove are therefore only guidelines.

Experimental Part

In the procedures described hereinafter the following abbreviations wereused: “ACN” stands for acetonitrile; “THF” stands for tetrahydrofuran;“DCM” stands for dichloromethane; “DIPE” stands for diisopropylether;“DMF” means N,N-dimethyl-formamide; “NMP” means N-methyl-2-pyrrolidone;“TFA” means trifluoroacetic acid; “TIS” means triisopropylsilane;“DIPEA” means diisopropylethylamine; “TMSOTf” means trimethylsilyltriflate and “MIK” means methyl isobutyl ketone. Extrelut™ is a productof Merck KgaA, Darmstadt, Germany, and is a short column comprisingdiatomaceous earth.

A. PREPARATION OF INTERMEDIATE COMPOUNDS EXAMPLE A.1

α-Bromo-methyl ester benzeneacetic acid (0.026 mole) was added dropwiseto a mixture of 1-(4-nitrophenyl)piperazine (0.028 mole) and Na₂CO₃(0.024 mole) in DMF (150 ml) while stirring. The mixture was stirred atroom temperature for 66 hours, poured out into ice water (500 ml) andstirred for 30 minutes. The precipitate was filtered off and dissolvedin DCM. The organic solution was dried, filtered and the solvent wasevaporated. This fraction was purified over silica gel on a glass filter(eluent: CH₂Cl₂/CH₃OH 99/1). The pure fractions were collected and thesolvent was evaporated. Part of this fraction was stirred in ethanol.The precipitate was filtered off and dried, yielding 0.04 g of(±)-methyl 4-(4-nitrophenyl)-α-phenyl-1-piperazineacetate (intermediate1, melting point 92° C.).

EXAMPLE A.2

A mixture of intermediate (1) (0.026 mole) and KOH (0.13 mole) inethanol (150 ml) was stirred at room temperature for 18 hours, heated at50° C. for 2.5 hours and cooled to room temperature. The precipitate wasfiltered off, stirred in 2-propanol, filtered off, washed three timeswith 2-propanol and dried. This fraction was stirred and refluxed in2-propanol. HCl/2-propanol 6N (19.94 ml) was added. The mixture wasstirred and refluxed, filtered warm and stirred in water (350 ml). Theprecipitate was filtered off and dried, yielding 5.94 g of(±)-4-(4-nitrophenyl)-α-phenyl-1-piperazineacetic acid monohydrate(intermediate 2).

EXAMPLE A.3

A mixture of intermediate (1) (0.0136 mole) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.02 mole) in DCM (125ml) was stirred for two hours to give mixture (1). A mixture of2,2,2-trifluoroethylamine (0.014 mole) in DCM (25 ml) was stirred.Triethylamine (1.5 g) was added and the mixture was stirred for 5minutes to give mixture (2). Mixtures (1) and (2) were combined. Theresulting mixture was stirred overnight and washed with water. Theorganic layer was separated, dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 98/2). The pure fractions werecollected and the solvent was evaporated. This fraction was purified bycolumn chromatography over silica gel (eluent: DCM/hexane/ethyl acetate50/20/30). The pure fractions were collected and the solvent wasevaporated, yielding 2.3 g(±)-4-(4-nitrophenyl)-α-phenyl-N-(2,2,2-trifluoroethyl)-1-piperazineacetamide(intermediate 3).

EXAMPLE A.4

A mixture of intermediate (3) (0.0054 mole) in methanol (150 ml) washydrogenated with Pd/C 10% (1 g) as a catalyst in the presence of a 4%thiophene solution (1 ml). After uptake of hydrogen (2 equivalents), thecatalyst was filtered off and the filtrate was evaporated. The residuewas triturated in DIPE. The precipitate was filtered off and dried,yielding 1.5 g of(±)-4-(4-aminophenyl)-α-phenyl-N-(2,2,2-trifluoroethyl)-1-piperazineacetamide(intermediate 4, melting point 136° C.).

EXAMPLE A.5

A mixture of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride(0.185 mole) in DCM (1500 ml) and triethylamine (50 ml) was stirred onan ice-bath for 5 minutes.4-[4-(Phenylmethyl)-1-piperazinyl]-benzenamine (0.37 mole) in DCM (500ml) was added dropwise. The mixture was stirred for 3 hours. The organiclayer was separated, washed with water, dried, filtered and the solventwas evaporated. The residue was triturated in DIPE. The precipitate wasfiltered off and dried, yielding 99.8 g ofN-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]-4′-(trifluoro-methyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 5, melting point 180° C.).

EXAMPLE A.6

A mixture of intermediate (5) (0.19 mole) in methanol (600 ml) and THF(600 ml) was hydrogenated overnight with Pd/C 10% (3 g) as a catalyst.After uptake of hydrogen (1 equivalent), the catalyst was filtered offand the filtrate was evaporated. The residue was triturated in DIPE. Theprecipitate was filtered off, dried, and dissolved in water. The mixturewas alkalinized with Na₂CO₃ and then extracted with DCM. The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was triturated in DIPE. The precipitate was filtered off anddried, yielding 40 g ofN-[4-(1-piperazinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 6).

EXAMPLE A.7

A mixture of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid(0.09 mole) in DCM (500 ml) and DMF (5 ml) was stirred. Ethanedioyldichloride (0.09 mole) was added dropwise. The mixture was stirred for 1hour to give mixture (1). A mixture of4-[1-(phenylmethyl)-4-piperidinyl]-benzenamine (0.046 mole) in DCM (500ml) and triethylamine (20 ml) was stirred on an ice-bath. Mixture (1)was added dropwise. The mixture was stirred and refluxed overnight, thencooled and washed with water. The organic layer was separated, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 98/2). Thepure fractions were collected and the solvent was evaporated. Theresidue was triturated in DIPE. The precipitate was filtered off anddried, yielding 5.6 g ofN-[4-[1-(phenylmethyl)-4-piperidinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 7, melting point 134° C.).

EXAMPLE A.8

A mixture of intermediate (7) (0.025 mole) in methanol (250 ml) washydrogenated at 50° C. overnight with Pd/C 10% (2 g) as a catalyst.After uptake of hydrogen (1 equivalent), the catalyst was filtered offand the filtrate was evaporated. The residue was triturated in DIPE. Theprecipitate was filtered off and dried. A part (0.2 g) of this fractionwas purified by high performance liquid chromatography over RP-18(eluent: (NH₄OAc 0.5%/CH₃CN 90/10)/CH₃OH/CH₃CN 75/25/0, 0/50/50, 0/0/100and 75/25/0; column: Hyperprep RP 100 Å 8 μm). The pure fractions werecollected and the solvent was evaporated, yielding 0.119 g ofN-[4-(4-piperidinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideacetate (1:2) (intermediate 8, melting point 150° C.).

EXAMPLE A.9

A mixture of 4-[4-(phenylmethyl)-1-piperazinyl]-benzenamine (0.12 mole)in THF (300 ml) and triethylamine (50 ml) was stirred.[1,1′-Biphenyl]-2-carbonyl chloride (0.12 mole) was added dropwise. Themixture was stirred overnight. The solvent was evaporated. The residuewas dissolved in DCM. The organic layer was separated, washed, dried,filtered and the solvent was evaporated. The residue was triturated inDIPE/2-propanol. The precipitate was filtered off and dried. A part (1g) of this fraction was purified by column chromatography over silicagel (eluent: CH₂Cl₂/CH₃OH 99/1). The pure fractions were collected andthe solvent was evaporated. The residue was triturated in DIPE. Theprecipitate was filtered off and dried, yielding 0.84 g ofN-[4-[4-(phenylmethyl)-1-piperazinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide(intermediate 9, melting point 162° C.).

EXAMPLE A.10

A mixture of intermediate (9) (0.1 mole) in methanol (500 ml) washydrogenated for two hours with palladium-on-carbon (10%) (10 g) as acatalyst. After uptake of hydrogen (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was trituratedin 2-propanol. The precipitate was filtered off and dried, yielding 29 gof N-[4-(1-piperazinyl)phenyl]-[1,1′-biphenyl]-2-carboxamide(intermediate 10, melting point 176° C.).

EXAMPLE A.11

a) A mixture of 4-(4-bromophenyl)-1-(phenylmethyl)-4-piperidinol (0.23mole) and Cu₂O (2 g) in aqueous ammonia (500 ml) was stirred at 180° C.for twelve hours. The mixture was cooled, extracted with DCM and washedwith water. The organic layer was dried, filtered off and evaporated,yielding 60 g of4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine.

b) [1,1′-Biphenyl]-2-carbonyl chloride (0.05 mole) was added dropwise toa stirring mixture of4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (0.045mole) in THF (300 ml) and triethylamine (25 ml). The mixture was stirredovernight. The solvent was evaporated. The residue was dissolved in DCM.The organic layer was separated, washed, dried, filtered and the solventwas evaporated. The residue was triturated in DIPE. The precipitate wasfiltered off and dried, yielding 18.5 g ofN-[4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide(intermediate 11, melting point 142° C.).

EXAMPLE A.12

A mixture of α-phenyl-4-piperidineacetonitrile hydrochloride (0.05mole), 1-fluoro-4-nitrobenzene (0.06 mole) and potassium carbonate (0.15mole) in DMF (200 ml) was stirred at 50° C. for four hours. Water andDIPE were added. The mixture was cooled. The precipitate was filteredoff, washed with water and DIPE and dried, yielding 11.6 g of(±)-1-(4-nitrophenyl)-α-phenyl-4-piperidine-acetonitrile (intermediate12, melting point 118° C.).

EXAMPLE A.13

A mixture of intermediate (12) (0.036 mole) in a 48% aqueous solution ofhydrogen bromide (100 ml) was stirred and refluxed for three hours,cooled, poured out into water and extracted twice with DCM. The organiclayer was separated, washed with water, dried, filtered and the solventwas evaporated. The residue was triturated with 2-propanol. Theprecipitate was filtered off and dried, yielding 9.5 g of(±)-1-(4-nitrophenyl)-α-phenyl-4-piperidineacetic acid (intermediate 13,melting point 216° C.).

EXAMPLE A.14

Thionyl chloride (0.01 mole) was added to a mixture of intermediate (13)(0.0029 mole) in DCM (10 ml). The mixture was stirred for one minuteovernight and then allowed to stand. The solvent was evaporated. Theresidue was dissolved in DCM (10 ml). Methanol (10 ml) was added. Themixture was allowed to stand for four hours, then poured out into aNaHCO₃ solution and extracted with DCM. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue wastriturated in hexane/DIPE. The precipitate was filtered off and dried,yielding 0.9 g of (±)-methyl1-(4-nitrophenyl)-α-phenyl-4-piperidineacetate (intermediate 14, meltingpoint 124° C.).

EXAMPLE A.15

A mixture of intermediate (14) (0.0022 mole) in methanol (100 ml) washydrogenated at 50° C. with palladium-on-carbon (10%) (0.1 g) as acatalyst in the presence of a 4% thiophene solution (0.1 ml). Afteruptake of hydrogen (3 equivalents), the catalyst was filtered off andthe filtrate was evaporated. The residue was triturated in hexane. Theprecipitate was filtered off and dried, yielding 0.7 g of (±)-methyl1-(4-aminophenyl)-α-phenyl-4-piperidineacetate (intermediate 15, meltingpoint 125° C.).

EXAMPLES A.16 TO A.18

In order to facilitate the understanding of these examples, thefollowing presents a scheme (scheme 1) of the preparation ofintermediate resins starting from a commercially available resin:

EXAMPLE A.16

Ethylamine (0.0056 mole; 2.8 ml of a 2 M solution in THF, thus R^(a)=ain scheme 1) was added to a Novabiochem 01-64-0261 commercial resin (1g) in DCM (15 ml). Titanium (IV) isopropoxide (1.65 ml) was added andthe mixture was shaken for one hour at room temperature. Triacetoxyborohydride (1.187 g) was added and the reaction mixture was shaken for48 hours at room temperature. The mixture was filtered, and the filterresidue was washed three times with DCM, three times with a (1:1)mixture of DCM and methanol, three times with firstly methanol, thensecondly with DCM, once with a mixture of 10 ml DCM and 2 ml DIPEA,three times with firstly DCM, then secondly with methanol, then dried,quantitatively yielding an ethylamino terminated resin identified as I-ain scheme 1, which is used in the next reaction step without furtherpurification.

EXAMPLE A.17

Intermediate (13) (0.0056 mole) was added to the resin of example A.16(0.00112 mole). A solution of a complex of (T-4)-hexafluorophosphate(¹⁻)(1-hydroxy-1H-benzotriazolato-O)tri-1-pyrrolidinyl-phosphorus(¹⁺)(hereinafter referred to as “PyBOP”) (2.9 g) in DCM (15 ml) and DMF (5ml) was added. Triethylamine (0.0112 mole) was added and the reactionmixture was shaken for 24 hours at room temperature, filtered and thefilter residue was washed with DMF (5×20 ml), then five times with (1:1)mixture of DCM and methanol (20 ml), five times with a (95:5) mixture ofDCM with acetic acid (20 ml), five times with DMF (20 ml) and threetimes with NMP (20 ml), quantitatively yielding a nitro terminated resinidentified as II-a in scheme 1.

EXAMPLE A.18

A mixture of the resin of example A.17 (0.00112 mole) and SnCl₂.2H₂O(0.0224 mole) in NMP (20 ml) was shaken for six days at 55° C., thencooled, filtered and the filter residue was washed with DMF (threetimes), with a mixture of 10 ml DMF and 2 ml DIPEA, and then three timeswith firstly DCM, followed by secondly methanol, then dried,quantitatively yielding an amino terminated resin identified as III-a inscheme 1.

EXAMPLE A.19

Triisopropylamine (0.011 mole) was added to the resin of example A.18(0.00112 mole) in DCM (10 ml). N,N-dimethyl-4-pyridinamine (0.0003 mole)in DCM (3 ml) was added. A solution of o-iodobenzoyl chloride (0.00336mole) in DCM (5 ml) was added and the reaction mixture was shakenovernight at room temperature. The mixture was filtered, the residue waswashed three times with DCM, once with a mixture of DCM (10 ml) andDIPEA (2 ml), three times with DCM then methanol, then dried. Theresulting product was treated with benzylamine (1 ml) in DCM (10 ml) andshaken for 60 hours at room temperature. The mixture was filtered,washed three times with DCM, once with DCM/methanol 50/50, three timeswith DCM then methanol, then dried, yielding 0.00515 g (46%) of a resinidentified as IV-a in scheme 1.

EXAMPLE A.20

The procedure of example A.16 is repeated while replacing ethylamine byn-propylamine, thus quantitatively yielding a n-propylamino terminatedresin identified as I-b in scheme 1.

EXAMPLE A.21

The first experimental procedure of example A.17 is repeated whilereplacing the resin of example A.16 by the resin of example A.20, thusquantitatively yielding the resin identified as II-b in scheme 1.

EXAMPLE A.22

The procedure of example A.18 is repeated while replacing the resin ofexample A.17 by the resin of example A.21, thus quantitatively yieldingthe resin identified as III-b in scheme 1.

EXAMPLE A.23

The procedure of example A.19 is repeated while replacing the resin ofexample A.18 by the resin of example A.22, thus yielding the resinidentified as IV-b in scheme 1.

EXAMPLE A.24

The procedure of example A.16 is repeated while replacing ethylamine byisopropylamine, thus quantitatively yielding an isopropylaminoterminated resin identified as I-c in scheme 1.

EXAMPLE A.25

The first experimental procedure of example A.17 is repeated whilereplacing the resin of example A.16 by the resin of example A.24, thusquantitatively yielding the resin identified as II-c in scheme 1.

EXAMPLE A.26

The procedure of example A.18 is repeated while replacing the resin ofexample A.17 by the resin of example A.25, thus quantitatively yieldingthe resin identified as III-c in scheme 1.

EXAMPLE A.27

The procedure of example A.19 is repeated while replacing the resin ofexample A.18 by the resin of example A.26, thus yielding the resinidentified as IV-c in scheme 1.

EXAMPLE A.28

The procedure of example A.16 is repeated while replacing ethylamine byphenylamine, thus quantitatively yielding a phenylamino terminated resinidentified as I-d in scheme 1.

EXAMPLE A.29

The first experimental procedure of example A.17 is repeated whilereplacing the resin of example A.16 by the resin of example A.28, thusquantitatively yielding the resin identified as II-d in scheme 1.

EXAMPLE A.30

The procedure of example A.18 is repeated while replacing the resin ofexample A.17 by the resin of example A.29, thus quantitatively yieldingthe resin identified as III-d in scheme 1.

EXAMPLE A.31

The procedure of example A.19 is repeated while replacing the resin ofexample A.18 by the resin of example A.30, thus yielding the resinidentified as IV-d in scheme 1.

EXAMPLE A.32

The procedure of example A.16 is repeated while replacing ethylamine bybenzylamine, thus quantitatively yielding a benzylamino terminated resinidentified as I-e in scheme 1.

EXAMPLE A.33

The first experimental procedure of example A.17 is repeated whilereplacing the resin of example A.16 by the resin of example A.32, thusquantitatively yielding the resin identified as II-e in scheme 1.

EXAMPLE A.34

The procedure of example A.18 is repeated while replacing the resin ofexample A.17 by the resin of example A.33, thus quantitatively yieldingthe resin identified as III-e in scheme 1.

EXAMPLE A.35

The procedure of example A.19 is repeated while replacing the resin ofexample A.18 by the resin of example A.34, thus yielding the resinidentified as IV-e in scheme 1.

EXAMPLES A.36 TO A.38

In order to facilitate the understanding of these examples, thefollowing presents another scheme (scheme 2) for the preparation ofintermediate resins starting from a commercially available resin:

EXAMPLE A.36

A mixture of commercial Novabiochem 01-64-0261 resin (25.1 g, 0.028mole), 4-bromoaniline (24 g, 0.140 mole) and titanium (IV) isopropoxide(41 ml, 0.140 mole) in DCM (400 ml) was stirred gently for one hour atroom temperature. Sodium triacetoxyborohydride (30 g, 0.140 mole) wasadded and the reaction mixture was stirred overnight at roomtemperature. Methanol (50 ml) was added and the mixture was stirred forone hour, then filtered, washed once with DCM, once with methanol, thenonce with DCM (200 ml)+DIPEA (20 ml), washed three times with firstlyDCM, followed secondly by methanol, then dried, yielding 29.28 g of aresin identified as V in scheme 2, which is used in the next reactionstep without further purification.

EXAMPLE A.37

4-Phenyl benzoic acid (8.3 g, 0.042 mole) was dissolved in DCM (100 ml).Thionyl chloride (10 g, 0.084 mole) was added. DMF (10 drops) was addedand the mixture was stirred and refluxed for one hour. The solvent wasevaporated. DCM (three times 50 ml) was added. The solvent wasevaporated. The residue was dissolved in DCM (50 ml). This solution wasadded to a mixture of the resin of example A.36 (14.64 g, 0.0133 mole),DIPEA (24 ml, 0.140 mole) and 4-dimethylaminopyridine (hereinafterreferred as DMAP) (0.5 g) in DCM (150 ml). The reaction mixture wasshaken overnight at room temperature, then filtered and the filterresidue was washed with 100 ml DMF+20 ml DIPEA, then with methanol,water, DCM, methanol, DCM and methanol, and dried, yielding 15.73 g of aresin identified as VI-a in scheme 2.

EXAMPLE A.38

4′-(Trifluoromethyl)-2-biphenyl carboxylic acid (14.64 g, 0.042 mole)was dissolved in DCM (100 ml). DMF (1 ml) was added. Thionyl chloride(10 g, 0.084 mole) was added and the mixture was stirred and refluxedfor one hour. The solvent was evaporated. DCM (twice 50 ml) was added,then the solvent was evaporated. The residue was dissolved in DCM (50ml). This solution was added to a mixture of the resin of example A.36(14.64 g, 0.0133 mole), DIPEA (24 ml, 0.140 mole) and DMAP (0.5 g) inDCM (150 ml). The reaction mixture was shaken for four hours at roomtemperature then filtered and the filter residue was washed with 100 mlDMF+20 ml DIPEA, then washed three times firtstly with DCM and secondlywith methanol, and finally dried. This reaction product was reacted oncemore with half the initial quantities of4′-(trifluoro-methyl)-2-biphenyl carboxylic acid, thionyl chloride,DIPEA and DMAP. The reaction mixture was shaken overnight at roomtemperature, then filtered, and the filter residue was shaken withDMF+20 ml DIPEA, then methanol, water, methanol, DCM, methanol, DCM andmethanol, then dried, yielding 17.48 g of a resin identified as VI-b inscheme 2.

EXAMPLE A.39

a) A mixture of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid(0.09 mol) in DCM (500 ml) and DMF (5 ml) was stirred. Ethanedioyldichloride (0.09 mol) was added dropwise. The mixture was stirred for 1hour to give mixture 1. A mixture of4-[1-(phenylmethyl)-4-piperidinyl]-benzenamine hydrochloride salt (1:1)(0.046 mol) in DCM (500 ml) and triethylamine (20 ml) was stirred on anice-bath. Mixture 1 was added dropwise. The mixture was stirred andrefluxed overnight, then cooled and washed with water. The organic layerwas separated, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 98/2). The pure fractions were collected and the solventwas evaporated. The residue was triturated in DIPE. The precipitate wasfiltered off and dried, yielding 5.6 g ofN-[4-[1-(phenylmethyl)-4-piperidinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 16, mp. 134° C.).

b) A mixture of intermediate (16) (0.025 mol) in methanol (250 ml) washydrogenated at 50° C. overnight with Pd/C 10% (2 g) as a catalyst.After uptake of hydrogen (1 equivalent), the catalyst was filtered offand the filtrate was evaporated. The residue was triturated in DIPE. Theprecipitate was filtered off and dried, yielding 7.7 gN-[4-(4-piperidinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 17).

EXAMPLE A.40

a) [1,1′-Biphenyl]-2-carboxylic acid (0.25 mol) was dissolved in DCM(500 ml) and DMF (0.5 ml). Thionyl chloride (0.51 mol) was addeddropwise. The mixture was stirred and refluxed for 1 hour under nitrogenflow. The solvent was evaporated. DCM (500 ml) was added twice. Thesolvent was evaporated twice. The residue was dissolved in DCM (200 ml)and then added dropwise at 0° C. to a mixture of4-[1-(phenylmethyl)-4-piperidinyl]-benzenamine (0.25 mol) andN-(1-methylethyl)-2-propanamine (0.75 mol) in DCM (800 ml). The mixturewas brought to room temperature and then stirred at room temperatureovernight under nitrogen flow. The mixture was washed three times withwater (800 ml). The organic layer was separated, dried, filtered and thesolvent was evaporated, yielding 125 g ofN-[4-[1-(phenylmethyl)-4-piperidinyl]phenyl]-[1,1′-biphenyl]-2-carboxamide(intermediate 18).

b) A mixture of intermediate (18) (0.145 mol) in methanol (500 ml) washydrogenated at 50° C. during 48 hours with Pd/C (10%, 3 g) as acatalyst. After uptake of hydrogen (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was trituratedin DIPE. The precipitate was filtered off and dried, yielding 49 g ofN-[4-(4-piperidinyl)phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate19).

EXAMPLE A.41

a) 4′-(Trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (0.12 mol)was added dropwise to a stirring mixture of4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine (0.095mol) in DCM (300 ml) and triethylamine (50 ml). The mixture was stirredovernight, poured out into water and then stirred for 30 minutes. Theorganic layer was separated, washed, dried, filtered and the solvent wasevaporated. The residue was triturated in DIPE. The precipitate wasfiltered off and dried, yielding 43 g ofN-[4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 20).

b) 1-Chloroethyl chloroformate (0.078 mol) was added dropwise to astirring mixture of intermediate (20) (0.039 mol) in 1,2-dichloro-ethane(500 ml). The mixture was stirred for 30 minutes and then stirred andrefluxed overnight. The solvent was evaporated. Methanol (500 ml) wasadded. The mixture was stirred and refluxed overnight. The solvent wasevaporated. The residue was triturated in DIPE. The precipitate wasfiltered off and dried, yielding 20.8 g ofN-[4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-4′-(trifluoro-methyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 21).

EXAMPLE A.42

A mixture of intermediate (11) (0.04 mol) in 1,2-dichloro-ethane (200ml) was stirred on an ice-bath. 1-Chloroethyl chloroformate (15 ml) wasadded dropwise at a temperature below 5° C. The mixture was stirred for1 hour and then stirred and refluxed overnight. The solvent wasevaporated. Methanol (200 ml) was added. The mixture was stirred andrefluxed for 2 hours. The solvent was evaporated. The residue wastriturated in DIPE. The precipitate was filtered off and dried, yield16.7 g ofN-[4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-[1,1′-biphenyl]-2-carboxamide(intermediate 22).

EXAMPLE A.43

a) A mixture of intermediate (6) (0.0047 mol) and di-tert-butyldicarbonate (0.0052 mol) in DCM (50 ml) was stirred at room temperaturefor 2 hours. DMF (5 ml) was added. The mixture was stirred at roomtemperature for 3 hours. The solvent was evaporated. The residue wasstirred in DIPE. The precipitate was filtered off and dried in vacuo at54° C., yielding 2.47 g of 1,1-dimethylethyl ester4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazinecarboxylicacid (intermediate 23, mp. 204° C.).

b) NaH 60% in mineral oil (0.0056 mol) was treated with hexane; stirredunder nitrogen flow and decanted. DMF dry (25 ml) was added to theresidue. The suspension was stirred at room temperature under nitrogenflow. A solution of intermediate (23) (0.00375 mol) in DMF dry (25 ml)was added dropwise. The mixture was stirred at room temperature undernitrogen flow for 2.5 hours. A solution of methyl methanesulfonate(0.0045 mol) in DMF dry (50 ml) was added dropwise. The mixture wasstirred at room temperature for 18 hours. Water (150 ml) was added. Themixture was extracted twice with DCM. The organic layer was separated,dried, filtered and the solvent was evaporated. The residue was stirredin 60 ml of hexane/DIPE (3:1). The mixture was stirred and refluxeduntil a clear solution was obtained and then brought to roomtemperature. The precipitate was filtered off and dried, yielding 1.6 gof 1,1-dimethylethyl ester4-[4-[methyl[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazinecarboxylicacid (intermediate 24).

c) A solution of trifluoroacetate (20 ml) and DCM (200 ml) was added tointermediate (24) (0.0024 mol) and stirred for 1 hour and 30 minutes atroom temperature. The solvent was evaporated. DCM was added and againthe solvent was evaporated, yielding 1.7 g ofN-methyl-N-[4-(1-piperazinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(intermediate 25).

EXAMPLE A.44

Intermediate resins wherein X₂ and X₃ represent N and Z₁ and Z₂represent —CH₂CH₂— can be prepared as depicted in scheme 3 starting froma commercially available resin:

a) A mixture of commercial Novabiochem 01-64-0261 resin (0.180 g, 0.002mol), 4-(1-tert-butoxycarbonylpiperazin-4-yl)aniline ((0.001 mol),dissolved in DCM (2 ml)) and titanium (IV) isopropoxide (0.001 mol) inDCM (3 ml) was shaken for 2 hours at room temperature. Sodiumtriacetoxyborohydride (0.001 mol) was added portionwise and the reactionmixture was shaken for 20 hours at room temperature. The mixture wasfiltered and the filter residue was washed three times with DCM (3times), methanol (3 times), and then three times with DCM, then dried,yielding resin (VII-a).

b) 2-Bromo-4-methylbenzoic acid (0.001 mol) in DCM (5 ml) with thionylchloride (0.013 mol) was stirred and refluxed for one hour. The mixturewas blown dry under nitrogen. Again, DCM (5 ml) with thionyl chloride(0.013 mol) was added. The reaction mixture was stirred and refluxed forone hour. The mixture was blown dry under nitrogen and three times withDCM (3 ml) was added, then evaporated again. The residue was dissolvedin DCM (3 ml). this solution was added to a solution of resin (VII-a)(0.0002 mol) in DCM (1 ml). DMAP (0.0002 mol) in DCM (1 ml) was added.DIPEA (0.002 mol) was added and the reaction mixture was shaken for 20hours at room temperature. The reaction mixture was filtered and thefilter residue was washed three times with DCM (3 times), methanol (3times), and then three times with DCM, then dried, yielding resin(VIII-a).

c) A solution of 4-(trifluoromethyl)benzeneboronic acid (0.0016 mol) indioxane (3 ml) was added to resin (VIII-a) (0.0002 mol) which waspreviously washed with dioxane (5 ml). Then, KOH (0.0032 mol of a 2 Msolution) was added and the reaction mixture was shaken for 30 minutesat room temperature under a nitrogen atmosphere. PdCl₂(PPh₃)₂ (0.00004mol) in NMP (0.5 ml) was added and the reaction mixture was shaken for 2hours at 90° C. Again, PdCl₂(PPh₃)₂ (0.00004 mol) in NMP (0.5 ml) wasadded and the reaction mixture was shaken for 2 hours at 90° C. Themixture was cooled, filtered and the filter residue was washed with DMF(3 times), with water (3 times), DMF (3 times), methanol (3 times), DCM(3 times), methanol (3 times) and DCM (3 times), then dried yielding aresidue. Said residue was stirred in a solution of TMSTf (1 M) and2,6-lutidine (1.5 M) in DCM (4 ml) for 2 hours at room temperature,filtered, and washed with DCM (3 times) and methanol (3 times), anddried, yielding resin (IX-a).

EXAMPLE A.45

a) A suspension of 4-(tert-butoxycarbonylamino)piperidine (15equivalents) in NMP (2 ml) was added to resin (VI-b) in NMP (1 ml).[1,1′-Binaphthalene]-2,2′-diylbis[diphenyl-phosphine (BINAP) (0.00011mol) was added portionwise. tert-Butoxysodium (15 equivalents) was addedportionwise. The reaction mixture was shaken for one hour under nitrogenflow. Pd₂(dba)₃ (0.000022 mol) in NMP (1 ml) was added and the reactionmixture was shaken for 18 hours at 105° C. The mixture was cooled,filtered and the filter residue was washed with three times (with DMFfollowed with water), and then three times with methanol, then DCM,yielding resin (X).

b) Resin (X) (0.00011 mol) was shaken in NMP (2 ml). Bromobenzene(0.00165 mol) in NMP (1 ml) was added. BINAP (0.068 g) was addedportionwise. Tert-butoxysodium (0.190 g) was added portionwise. Themixture was shaken for 1 hour under nitrogen. Pd₂(dba)₃ (0.020 g) in NMP(1 ml) was added and the reaction mixture was shaken for 18 hours at105° C., then cooled, filtered and the filter residue was washed withthree times (with DMF followed with water), and then three times withmethanol, then DCM yielding resin (XI).

EXAMPLE A.45

Resin (XI) (0.0002 mol) was washed with DCM (4 ml), then filtered off,then dissolved in DCM (5 ml). Trichloromethyl chloroformate (0.001 mol)was added and the reaction mixture was shaken for 4 hours at roomtemperature. The mixture was filtered, washed three times with DCM, thendried, yielding resin (XII).

EXAMPLE A.46

a) 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl)(0.096 mol) was added at room temperature to a mixture of4-(4-aminophenyl)-1-piperazinecarboxylic acid ethyl ester (0.08 mol),2-iodo benzoic acid (0.096 mol) and 1-hydroxybenzotriazole (HOBT) (0.096mol) in DCM (500 ml). The mixture was stirred at room temperatureovernight. Water was added. The mixture was extracted with DCM. Theorganic layer was separated, dried, filtered, and the solvent wasevaporated. The residue was taken up in DIPE. The precipitate wasfiltered off and dried, yielding 39 g of4-[4-[(2-iodobenzoyl)-amino]phenyl]-1-piperazinecarboxylic acid, ethylester (intermediate 27).

b) A mixture of intermediate (27) (0.041 mol) and potassium hydroxide(0.41 mol) in isopropanol (200 ml) was stirred and refluxed for 3 hoursand the solvent was evaporated till dryness. Water was added. Themixture was extracted with DCM and the solvent was evaporated, yielding2-iodo-N-[4-(1-piperazinyl)phenyl]benzamide (intermediate 28).

c) α-Bromo-benzeneacetic acid methyl ester (0.0123 mol) was added atroom temperature to a mixture of intermediate (28) (0.0123 mol) andNa₂CO₃ (0.0123 mol) in DMF (50 ml). The mixture was stirred at roomtemperature for 2 hours. Water was added. The mixture was stirred atroom temperature for 15 minutes. The precipitate was filtered, washedwith diethyl ether and dried, yielding 5.8 g of4-[4-[(2-iodobenzoyl)amino]phenyl]-α-phenyl-1-piperazine-acetic acid,methyl ester (intermediate 29).

d) A mixture of intermediate (29) (0.0036 mol),tributyl-2-furanyl-stannane (0.029 mol), PdCl₂(PPh₃)₂ (0.0007 mol) andNa2CO3 (0.0576 mol) in dioxane (30 ml) was stirred and refluxed for 1hour. Water was addedd. The mixture was extracted with ethyl acetate.The organic layer was separated, dried, filtered, and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: cyclohexane/ethyl acetate 80/20). The pure fractionswere collected and the solvent was evaporated, yielding4-[4-[[2-(2-furanyl)benzoyl]amino]phenyl]-α-phenyl-1-piperazineaceticacid, methyl ester (intermediate 30, mp. 90° C.).

e) A mixture of intermediate (30) (0.0006 mol) and potassium hydroxide(0.006 mol) in isopropanol (5 ml) was stirred at room temperatureovernight. The solvent was evaporated. The residue was dissolved inisopropanol/HCl 6N and converted into the hydrochloric acid salt. Theprecipitate was filtered off and dried, yielding 0.31 g of4-[4-[[2-(2-furanyl)benzoyl]amino]phenyl]-α-phenyl-1-piperazineaceticacid (intermediate 31).

B. PREPARATION OF POLYARYLCARBOXAMIDE COMPOUNDS OF THE INVENTION EXAMPLEB.1

A mixture of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid(0.012 mole) in DCM (100 ml) and DMF (8 drops) was stirred. Ethanedioyldichloride (0.012 mole) was added. The mixture was stirred for 2 hours,to give mixture (I). Triethylamine (8 ml) was added to a mixture ofintermediate (4) (0.005 mole) in DCM (100 ml). The mixture was stirredon an ice-salt bath to give mixture (II). Mixture (I) was added dropwiseto mixture (II) and the resulting reaction mixture was stirred andrefluxed for two days. The solvent was evaporated. The residue wasdissolved in DCM. The organic layer was separated, washed, dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: DCM/CH₃OH 99/1). Thedesired fractions were collected and the solvent was evaporated. Theresidue was triturated in DIPE. The precipitate was filtered off anddried, yielding 2.99 g ofN-[4-[4-[2-oxo-1-phenyl-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-piperazinyl]-phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(melting point 208° C.) identified as compound No. 1 in the followingtable F-1.

EXAMPLE B.2

Fluorene-4-carboxylic acid (0.00032 mole) in 1 ml of 1/1-mixture ofDCM/NMP was added to PyBOP (0.00064 mole) in DCM (1 ml). This mixturewas stood for 30 minutes, then added to the resin of example A.34. DCM(5 ml) was added, followed by DIPEA (0.00085 mole). The reaction mixturewas shaken for 24 hours at room temperature, then filtered, washed 3times with DCM, 3 times with methanol, followed by DCM. A mixture ofTFA/DCM/TIS (5/93/2) (4 ml) was added and the mixture was shaken for onehour at room temperature. The mixture was filtered, the filter residuewas washed with a mixture of TFA/DCM/TIS (5/93/2) (2 ml) and with DCM (2ml). The filtrate was blown dry at 50° C. under a gentle stream ofnitrogen gas, dissolved in DCM (5 ml) and DMF (1 ml) and a Novabiochem01-64-0171 resin was added while stirring the mixture at roomtemperature. Then, after one hour, an Argonaut P/N 800277 resin (0.040g) was added. The mixture was stirred for four hours at roomtemperature, filtered, and the filtrate was blown dry at 50° C. under anitrogen flow, yielding 0.027 g of the compound identified as No. 2 inthe following table F-1.

Compounds identified as No. 3 to No. 11 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing fluorene-4-carboxylic acid by the appropriate reactive acid.

EXAMPLE B.3

Fluorene-4-carboxylic acid (0.00028 mole) in 1 ml of a 1/1 mixture ofDCM/NMP was added to PyBOP (0.00028 mole) in DCM (1 ml). This mixturewas stood for 30 minutes, then added to the resin of example A.22. DCM(5 ml) was added, followed by triethylamine (0.00057 mole). The reactionmixture was shaken for 20 hours at room temperature, then filtered,washed three times with DCM, three times with first methanol, followedby secondly DCM. 4 ml of a mixture of TFA/DCM/TIS (5/93/2) was added andthe mixture was shaken for one hour at room temperature. The mixture wasfiltered, the filter residue was washed with a mixture of TFA/DCM/TIS (2ml; 5/93/2) and with DCM (1 ml). The filtrate was blown dry at 50° C.under a gentle stream of nitrogen. This fraction was purified by highperformance liquid chromatography over Hyperprep RP-C18 BDS (100 g, 100Å, 8 μm; eluent: [(0.5% NH₄OAc in H₂O)/CH₃CN 90/10)]/CH₃OH/CH₃CN (0minutes) 75/25/0, (10 minutes) 0/50/50, (16 minutes) 0/0/100,(18.10-20.00 minutes) 75/25/0). The pure fractions were collected andthe organic solvent was evaporated. The aqueous concentrate wasextracted with DCM/aqueous K₂CO₃ solution, then separated overExtrelut™. The organic phase was blown dry under nitrogen at 50° C. Theresidue was dried further under vacuum at 60° C., yielding 0.002 g ofthe compound identified as No. 12 in the following table F-1.

Compounds identified as No. 13 to No. 20 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing fluorene-4-carboxylic acid by the appropriate reactive acid.

EXAMPLE B.4

Fluorene-4-carboxylic acid (0.00015 mole) in 1 ml of 1/1 mixture ofDCM/NMP was added to PyBOP (0.0003 mole) in DCM (1 ml). This mixture wasstood for 30 minutes, then added to the resin of example A.26. DCM (5ml) was added, followed by DIPEA (0.00057 mole). The reaction mixturewas shaken for 24 hours at room temperature, then filtered, washed threetimes with DCM, three times with first methanol, followed by secondlyDCM. 4 ml of a mixture of TFA/DCM/TIS (5/93/2) was added and the mixturewas shaken for one hour at room temperature. The mixture was filtered,the filter residue was washed with 2 ml of a mixture of TFA/DCM/TIS(5/93/2) and with DCM (1 ml). The filtrate was blown dry at 50° C. undera gentle stream of nitrogen. This fraction was purified by highperformance liquid chromatography over Hyperprep C18 BDS (100 g, 100 Å,8 μm; eluent: [(0.5% NH₄OAc in H₂O)/CH₃CN 90/10)]/CH₃OH/CH₃CN (0 minute)75/25/0, (10 minute) 0/50/50, (16 minute) 0/0/100, (18.10-20.00 minute)75/25/0). The pure fractions were collected and the organic solvent wasevaporated. The aqueous concentrate was extracted with DCM/aqueouspotassium carbonate solution, then separated over Extrelut™. The organicphase was blown dry under nitrogen at 50° C. The residue was driedfurther under vacuum at 60° C., yielding 0.002 g of the compoundidentified as No. 21 in the following table F-1.

Compounds identified as No. 22 to No. 28 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing fluorene-4-carboxylic acid by the appropriate reactive acid.

EXAMPLE B.5

Fluorene-4-carboxylic acid (0.00023 mole) in 1 ml of 1/1 mixture ofDCM/NMP was added to PyBOP (0.00046 mole) in DCM (1 ml). This mixturewas stood for 30 minutes, then added to the resin of example A.30. DCM(5 ml) was added, followed by DIPEA (0.00057 mole). The reaction mixturewas shaken for 24 hours at room temperature, then filtered, washed threetimes with DCM, three times with first methanol, followed by secondlyDCM. A mixture of TFA/DCM/TIS (4 ml; 75/23/2) was added and the mixturewas shaken for one hour at room temperature. The mixture was filtered,the filter residue was washed with 2 ml of a mixture of TFA/DCM/TIS(75/23/2) and with DCM (2 ml). The filtrate was blown dry at 50° C.under a gentle stream of nitrogen. The residue was dissolved in DCM (5ml), then blown dry once more. This fraction was purified by highperformance liquid chromatography over Hyperprep RP-C18 BDS (100 g, 100Å, 8 μm; eluent: [(0.5% NH₄OAc in H₂O)/CH₃CN 90/10)]/CH₃OH/CH₃CN (0minute) 75/25/0, (10 minutes) 0/50/50, (16 minutes) 0/0/100,(18.10-20.00 minutes) 75/25/0). The pure fractions were collected andthe organic solvent was evaporated. The aqueous concentrate wasextracted with DCM/aqueous potassium carbonate solution, then separatedover Extrelut™. The organic phase was blown dry under nitrogen at 50° C.The residue was dried further under vacuum at 60° C., yielding 0.0046 gof the compound identified as No. 29 in the following table F-1.

Compounds identified as No. 30 to No. 36 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing fluorene-4-carboxylic acid by the appropriate reactive acid.

EXAMPLE B.6

A mixture of the Novabiochem 01-64-0261 commercial resin (0.00011 mole),intermediate (15) (0.00061 mole) and isopropyl titanate (0.18 ml) in DCM(5 ml) was shaken for one hour at room temperature. Triacetoxyborohydride (0.128 g) was added and the reaction mixture was shaken for16 hours at room temperature. Methanol (1 ml) was added and the mixturewas shaken for 5 minutes, then filtered, washed three times with DCM,methanol and dried under vacuum, yielding a residue (1).

Thionyl chloride (0.0020 mole) was added to4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.00055 mole) inDCM (2 ml) and the mixture was refluxed for 30 minutes while stirringfollowed by evaporation of the solvent. The residue was dissolved in DCM(5 ml) and the solution was added to the above-prepared residue (1).DIPEA (0.0011 mole) was added, followed by the addition ofN,N-dimethyl-4-pyridinamine (0.00008 mole). The reaction mixture wasshaken for 21 hours at room temperature, then filtered, washed threetimes with DCM, then three times with first a 4% acetic acid/DCMmixture, secondly DCM and finally three times with first DCM andsecondly methanol, then dried, and 4 ml of a mixture of TFA/DCM/TIS(49/49/2) was added. This mixture was shaken for one hour, filtered,washed with 2 ml of a mixture of TFA/DCM/TIS (49/49/2) and DCM (2 ml).The filtrate was blown dry with nitrogen at 50° C. DCM (5 ml) was added,then removed under a nitrogen stream at 50° C., yielding 0.080 g ofmethylα-phenyl-1-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetatetrifluoroacetate (1:1) identified as compound No. 37 in the followingtable F-1.

EXAMPLE B.7

4′-(Trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.00033 mole)and PyBOP (0.171 g) were dissolved in DCM (5 ml). This mixture was addedto the resin of example A.22 (0.00066 mole). DIPEA (0.00066 mole) wasadded and the reaction mixture was shaken for 48 hours at roomtemperature, filtered and the residue was washed three time with DMF,then three times with DCM and methanol, dried, yielding a residue. Saidresidue and a TFA/DCM/TIS (5:93:2) (4 ml) was shaken for 30 minutes atroom temperature, then filtered, washed with a mixture of TFA/DCM/TIS(5/93/2) (2 ml) and DCM (2 ml), then the filtrates were blown dry withnitrogen gas at 50° C., then dried further under vacuum at 60° C.,yielding 0.030 g ofN-[4-[4-[2-oxo-1-phenyl-2-(propylamino)ethyl]-1-piperidinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamidetrifluoroacetate (1:1) identified as compound No. 38 in the followingtable F-1.

EXAMPLE B.8

DMF (0.5 ml) was added to a solution of4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.014 mole) inDCM (50 ml) and thionyl chloride (0.028 mole). The mixture was stirredand refluxed for one hour. The solvent was evaporated. DCM (50 ml) wasadded twice and the solvent was evaporated. The residue was dissolved inDCM (20 ml) and this solution was added to a mixture of intermediate(15) (0.014 mole) and DIPEA (0.028 mole) in DCM (80 ml). The mixture wasstirred at room temperature for three hours and washed with water. Theorganic layer was dried and the solvent was evaporated. The residue wascrystallized from 2-propanol. The precipitate was filtered off anddried, yielding 6.2 g of methylα-phenyl-1-[4-[[[4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineacetate(melting point 151° C.) identified as compound No. 39 in the followingtable F-1.

EXAMPLE B.9

A mixture of intermediate (6) (0.023 mole) and Na₂CO₃ (0.023 mole) inDMF (150 ml) was stirred. Methyl α-bromo-α-phenylacetate (0.023 mole)was added dropwise. The mixture was stirred overnight. The solvent wasevaporated. The residue was dissolved in DCM. The organic layer wasseparated, washed, dried, filtered and the solvent was evaporated. Theresidue was triturated in DIPE. The precipitate was filtered off anddried, yielding 11.4 g of methylα-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazineacetateidentified as compound No. 40 in the following table F-1.

EXAMPLE B.10

A mixture of intermediate (8) (0.018 mole) and Na₂CO₃ (0.03 mole) in DMF(100 ml) was stirred. Methyl α-bromo-α-phenylacetate (0.025 mole) wasadded dropwise. The mixture was stirred overnight. The solvent wasevaporated. The residue was dissolved in DCM. The organic layer wasseparated, washed, dried, filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH 99/1). The pure fractions were collected and the solventwas evaporated, yielding 7.2 g ofmethylphenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperidineacetate(melting point 138° C.) identified as compound No. 41 in the followingtable F-1.

EXAMPLE B.11

Methyl α-bromo-α-phenylacetate (0.1 mole) was added dropwise to astirring mixture of intermediate (10) (0.07 mole) and Na₂CO₃ (13 g) inDMF (300 ml). The mixture was stirred overnight. The solvent wasevaporated. The residue was crystallized from methanol. The precipitatewas filtered off and dried, yielding 30.2 g of methyl4-[4-[([1,1′-biphenyl]-2-ylcarbonyl)amino]phenyl]-α-phenyl-1-piperazineacetate(melting point 125° C.) identified as compound No. 52 in the followingtable F-1.

EXAMPLE B.12

a) A mixture of compound (40) (0.19 mole) in HCl (36%) (100 ml) wasstirred and refluxed for five hours, then stirred overnight at roomtemperature. The precipitate was filtered off and triturated under2-propanol, filtered off and dried, yielding 5 g of the intermediatecompoundα-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]piperazineaceticacid monohydrochloride.

b) A mixture of the intermediate compound obtained in step (a) (0.00016mole), PyBOP (0.00032 mole) and triethylamine (0.1 ml) in DCM (5 ml) wasstirred for 30 minutes. Ethylamine (0.0005 mole) was added and thereaction mixture was stirred overnight at 40° C. The reaction mixturewas cooled. Water (2 ml) was added and the mixture was stirred for 15minutes, then filtered through Extrelut™, and the desired compound wasisolated by high performance liquid chromatography, yielding 0.046 g ofN-[4-[4-[2-(ethylamino)-2-oxo-1-phenylethyl]-1-piperazinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide(melting point 123° C.) identified as compound No. 54 in the followingtable F-1.

Compounds identified as No. 55 to No. 61 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing ethylamine by the appropriate reactive amine.

EXAMPLE B.13

A mixture ofα-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-phenyl]-1-piperazineaceticacid monohydrochloride (0.011 mole) in sulfuric acid (10 ml) andpropanol (150 ml) was stirred and refluxed overnight. The solvent wasevaporated. The residue was dissolved in DCM and washed with a solutionof Na₂CO₃. The organic layer was separated, washed, dried, filtered andthe solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂Cl₂/CH₃CN 95/5). The purefractions were collected and the solvent was evaporated. The residue wastriturated in DIPE. The precipitate was filtered off and dried, yielding2.6 g ofpropyl-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperazineacetate(melting point 151° C.) identified as compound No. 62 in the followingtable F-1.

EXAMPLE B.14

A mixture of intermediate (6) (0.017 mole) and ethyl 2-phenylacrylate(0.017 mole) in DMF (100 ml) was stirred for two days. Na₂CO₃ (1 g) wasadded. The mixture was stirred for two days. The solvent was evaporated.The residue was dissolved in DCM. The organic layer was separated,washed, dried, filtered and the solvent was evaporated. The residue wastriturated in DIPE. The precipitate was filtered off and dried, yielding10.6 g ofethylphenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]-phenyl]-1-piperazinepropanoate (melting point 195° C.) identified as compound No. 81 in thefollowing table F-1.

EXAMPLE B.15

a) A mixture of compound No. 81 (0.016 mole) in HCl (36%) (100 ml) wasstirred and refluxed for eight hours, then cooled and filtered. Theresidue was triturated in 2-propanol. The precipitate was filtered offand dried. A part (0.2 g) of this fraction was purified by highperformance liquid chromatography over RP-18 eluent: (NH₄OAc 0.5%/CH₃CN90/10)/CH₃OH/CH₃CN 75/25/0, 0/50/50 and 75/25/0; column: HYPERPREP 8μm). The pure fractions were collected and the solvent was evaporated.The residue was triturated in DIPE. The precipitate was filtered off anddried, yielding 0.12 g of the intermediate compound2-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2yl]carbonyl]amino]phenyl]-1-piperazinepropanoicacid (melting point 202° C.).

b) A mixture of the intermediate compound obtained in step (a) (0.00016mole), PyBOP (0.00032 mole) and triethylamine (0.1 ml) in DCM (5 ml) wasstirred for 30 minutes. Propylamine (0.0004 mole) was added and thereaction mixture was stirred overnight at 40° C. The reaction mixturewas cooled, washed with water (2 ml), then filtered through Extrelut™,and the extract's solvent was evaporated. The desired compound wasisolated by high performance liquid chromatography over Hyperprep RP-C18BDS (100 g, 100 Å, 8 μm; eluent: [(0.5% NH₄OAc in H₂O)/CH₃CN90/10)]/CH₃OH/CH₃CN (0 min) 75/25/0, (10 min) 0/50/50, (16 min) 0/0/100,(18.10-20.00 min) 75/25/0). The pure fractions were collected and thesolvent was evaporated, yielding ofN-[4-[4-[3-oxo-2-phenyl-3-(propylamino)propyl]-1-piperazinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideidentified as compound No. 63 in the following table F-1.

Compounds identified as No. 64 to No. 67 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing propylamine by the appropriate reactive amine.

EXAMPLE B.16

a) A mixture of compound No. 41 (0.012 mole) in HCl (36%) (100 ml) wasstirred and refluxed for six hours, then stirred overnight at roomtemperature. The precipitate was filtered off and triturated under2-propanol. The precipitate was filtered off and dried, yielding 6.2 gof the intermediate compoundα-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperidineaceticacid monohydrochloride.

b) A mixture of the intermediate compound obtained in step (a) (0.00017mole), PyBOP (0.3 g) and triethylamine (0.1 ml) in DCM (5 ml) wasstirred for 30 minutes. Ethylamine (0.00017 mole) was added. Thereaction mixture was stirred overnight at 40° C., then cooled and water(2 ml) was added. The mixture was stirred for one hour, then filteredthrough Extrelut™, and the filtrate was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH90/10). The product fractions were collected and the solvent wasevaporated, yielding 0.010 g ofN-[4-[1-[2-(ethylamino)-2-oxo-1-phenylethyl]-4-piperidinyl]phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamideidentified as compound No. 69 in the following table F-1.

Compounds identified as No. 70 to No. 80 in the following table F-1 weresimilarly prepared while using the same experimental procedure andreplacing ethylamine by the appropriate reactive amine.

EXAMPLE B.17

The resin of example A.23 (0.000045 mole) was washed twice with dioxane.1,4-Dioxane (1 ml) was added. 2,4-Difluorophenylboronic acid (0.0004mole) in 1,4-dioxane (1 ml) was added. KOH (2 M) (0.25 ml) was added.The mixture was shaken for 30 minutes under an argon atmosphere.PdCl₂(PPh₃)₂ (0.00001 mole) in NMP (0.250 ml) was added. The mixture wasstirred for 90 minutes at 98° C. Again, PdCl₂(PPh₃)₂ was added and thereaction mixture was warmed for 90 minutes at 98° C. The mixture wasallowed to cool to room temperature, then filtered and the filterresidue was washed three times with dioxane, three times with water andthree times with methanol, then three times with DCM then methanol,finally three times with DCM. F (4 ml) was added. The mixture was shakenfor 30 minutes, filtered, washed with TFA/DCM/TIS (2 ml, 5/93/2) and DCM(2 ml), and the filtrates were blown dry with a stream of nitrogen. Theresidue was purified by high performance liquid chromatography overPurospher Star RP-18 (20 g, 5 μm; eluent: ((0.5% NH₄OAc in H₂O)/CH₃CN90/10)/CH₃OH/CH₃CN (0 min) 75/25/0, (10.00 min) 0/50/50, (16.00 min)0/0/100, (18.10-20 min) 75/25/0). The desired fractions were collectedand the organic solvent was evaporated. The aqueous concentrate wasextracted with CH₂Cl₂/Na₂CO₃ solution. The extract was purified throughExtrelut™ and the organic phase was blown dry with a stream of nitrogen.The residue was dried under vacuum at 60° C., yielding 0.008 g of2′,4′-difluoro-N-[4-[4-[2-oxo-1-phenyl-2-(propylamino)ethyl]-1-piperidinyl]phenyl]-[1,1′-biphenyl]-2-carboxamideidentified as compound No. 84 in the following table F-1.

Compound identified as No. 68 in the following table F-1 was similarlyprepared while using the same experimental procedure.

EXAMPLE B.18

The resin of example A.19 (0.0001 mole) was washed three times withdioxane. 1,4-Dioxane (3 ml) was added. 2-Methylphenylboronic acid(0.0008 mole) in dioxane (1 ml) was added. KOH (2 M) (0.8 ml) was added.The mixture was shaken for 30 minutes under argon atmosphere.PdCl₂(PPh₃)₂ (0.00002 mole) in NMP (0.5 ml) was added. The mixture wasshaken for two hours at 96° C. Again, PdCl₂(PPh₃)₂ in 0.5 ml of NMP wasadded and the mixture was warmed for two hours at 96° C. The mixture wasallowed to cool to room temperature, then filtered and the filterresidue was washed three times with DMF, three times with H2O, threetimes with DMF, three times with methanol, three times with DCM, threetimes with methanol, and three times with methanol. A mixture ofTFA/DCM/TIS (4 ml) was added. The mixture was shaken for 60 minutes atroom temperature, filtered, washed with a mixture of TFA/DCM/TIS (2 ml)and DCM (2 ml), and the filtrates were blown dry with a stream ofnitrogen. The residue was purified by high performance liquidchromatography over Purospher Star RP-18 (20 g, 5 μm; eluent: ((0.5%NH₄OAc in H₂O)/CH₃CN 90/10)/CH₃OH/CH₃CN (0 min) 75/25/0, (10.00 min)0/50/50, (16.00 min) 0/0/100, (18.10-20 min) 75/25/0), yielding 0.004 gofN-[4-[4-[2-(ethylamino)-2-oxo-1-phenylethyl]-1-piperidinyl]phenyl]-2′-methyl-[1,1′-biphenyl]-2-carboxamideidentified as compound No. 85 in the following table F-1.

Compounds identified as No. 86 to No. 96 in the following table F-1 weresimilarly prepared while using the same experimental procedure.

EXAMPLE B.19

Argon gas was bubbled through a mixture of the resin of example A.23(0.0001 mole) and 3,5-dichlorobenzeneboronic acid (0.0008 mole) in K₂CO₃(2M in H₂O) (0.0008 mole) and 1,4-dioxane (5 ml) for five minutes.Palladium (II) acetate (0.00001 mole) in dioxane (0.5 ml) was added andthe reaction mixture was warmed and shaken for sixteen hours at 97° C.,then cooled, filtered, washed with DMF (three times), water (threetimes), DMF (three times), then three times with firstly methanol andsecondly DCM. A mixture of TFA/DCM/TIS (4 ml, 5/93/2) was added and themixture was shaken for one hour then filtered. A mixture of TFA/DCM/TIS(2 ml, 5/93/2) was added. The mixture was shaken for 10 minutes, thenfiltered, washed with DCM (3 ml) and the filtrate was blown dry undernitrogen at 50° C. The residue was purified by HPLC over Purospher StarRP-18-e (20 g, 5 μm; eluent: ((0.5% NH₄OAc in H₂O)/CH₃CN90/10)/CH₃OH/CH₃CN (0 min) 75/25/0, (10.00 min) 0/50/50, (16.00 min)0/0/100, (18.10-20 min) 75/25/0). The desired fractions were collectedand the organic solvent was evaporated. The aqueous concentrate wasextracted with CH₂Cl₂/aqueous K₂CO₃ solution. The extract was purifiedthrough Extrelut™ and the organic phase was blown dry with a stream ofnitrogen. The residue was dried under vacuum at 60° C., yielding 0.008 gof3′,5′-dichloro-N-[4-[4-[2-oxo-1-phenyl-2-(propylamino)ethyl]-1-piperidinyl]phenyl]-[1,1′-biphenyl]-2-carboxamideidentified as compound No. 97 in the following table F-1.

Compounds identified as No. 42 to 51, 53, 82, 83, and 98 to 118 in thefollowing table F-1 were similarly prepared while using the sameexperimental procedure.

EXAMPLE B.20

a) A suspension of 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (0.086 g,0.00014 mole) in NMP (1 ml) was added to the resin of example A.38 (0.2g, 0.00014 mole) and sodium terbutoxide (0.242 g, 0.00252 mole).Homopiperazine (0.126 g, 0.0021 mole) in NMP (2 ml) was added and themixture was stirred under argon. Tris(dibenzylidene acetone)di-palladium (0.026 g, 0.000028 mole) in NMP (1 ml) was added and thereaction mixture was shaken for 19 hours at 105° C. The mixture wascooled, filtered and the filter residue was washed with DMF, water, DMF(three times), H₂O (three times), DMF (three times), CH₃OH (threetimes), CH₂Cl₂ (three times), CH₃OH (three times) and NMP (two times).NMP (3 ml) was added.

b) Methyl-bromophenylacetate (0.16 g, 0.0007 mole) in NMP (1 ml) wasadded to the product obtained in step (a). DIPEA (0.3 ml) was added andthe mixture was shaken for 18 hours at room temperature. The mixture wasfiltered, washed with DMF and water, then with DMF (three times), water(three times), DMF (three times), methanol (three times), DCM (threetimes), methanol (three times) DCM (three times).

TFA/TIS/CH₂Cl₂ (49/2/49) (4 ml) was added and the mixture was shaken forone hour at room temperature. The mixture was filtered and moreTFA/TIS/CH₂Cl₂ (49/2/49) (1.5 ml) was added. The mixture was shaken for15 minutes, filtered, washed with DCM (2 ml), then the filtrates wereblown dry under nitrogen. The residue was purified by high performanceliquid chromatography over Purospher Star RP-18 (20 g, 5 μm; eluent:((0.5% NH₄OAc in H₂O)/CH₃CN 90/10)/CH₃CN/CH₃OH (0 min) 75/25/0, (10.00min) 0/50/50, (16.00 min) 0/0/100, (18.10-20 min) 75/25/0). The desiredfractions were collected and the organic solvent was evaporated. Theaqueous concentrate was treated with an aqueous sodium carbonatesolution, then extracted with DCM. The extract was separated throughExtrelut™ and the filtrates were blown dry under nitrogen at 50° C.,yielding 0.021 g of the compound identified as compound 119 in thefollowing table F-1.

Compounds identified as No. 120 to No. 128 in the following table F-1were similarly prepared while using the same experimental procedure.

EXAMPLE B.21

A mixture of intermediate (17) (0.019 mol) and Na₂CO₃ (0.019 mol) in DMF(125 ml) was stirred at room temperature. Methyl α-bromo-α-phenylacetate(0.01907 mol) was added dropwise. The mixture was stirred for 3 hours.The solvent was evaporated. The residue was taken up in water and DCM.The separated organic layer was dried, filtered and the solvent wasevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 100/0; 99.5/0.5). The pure fractionswere collected and the solvent was evaporated yielding a residue thatseparated in its enantiomers by high performance liquid chromatographyover Chiralpak AD (eluent: hexane/ethanol 70/30). The desired fractionswere collected and the solvent was evaporated, yielding, aftercrystallisation from 2-propanol, compound (229), mp. 158° C., [α]_(D)²⁰=−28.86° (c=24.95 mg/5 ml in CH₃OH); and compound (230), mp. 160° C.,[α]_(D) ²⁰=+27.69° (c=24.95 mg/5 ml in CH₃OH).

EXAMPLE B.22

Methyl α-bromo-α-phenylacetate (0.0010 mole) in NMP (1 ml) was added toresin (IX-a) (0.0002 mol) in NMP (3 ml). N,N-diisopropylethylamine(0.0023 mol) was added and the reaction mixture was shaken for 48 hoursat room temperature, then filtered and the filter residue was washedwith DMF (3 times), water (3 times), DMF (3 times), methanol (3 times),DCM (3 times), methanol (3 times) and DCM (3 times). A mixture ofTFA/TIS/CH₂Cl₂ (49/2/49) (4 ml) was added. the reaction mixture wasshaken for 2 hours at room temperature, then filtered and again amixture of TFA/TIS/CH₂Cl₂ (49/2/49) (4 ml) was added. The reactionmixture was shaken for another 15 minutes, then filtered and thefiltrates were blown dry under nitrogen. The residue was purified byhigh performance liquid chromatography over Purospher Star RP-18 (20 g,5 μm; eluent: ((0.5% NH₄OAc in H₂O)/CH₃CN 90/10)/CH₃CN/CH₃OH (0 min)75/25/0, (10.00 min) 0/50/50, (16.00 min) 0/0/100, (18.10-20 min)75/25/0). The desired fractions were collected and the organic solventwas evaporated. The aqueous concentrate was treated with an aqueoussodium carbonate solution, then extracted with DCM. The extract wasseparated through Extrelut™ and the filtrates were blown dry undernitrogen at 50° C., yielding compound (184) in the following table F-1.

EXAMPLE B.23

Dimethylallyl alcohol (0.00017 mol) was added to a mixture ofα-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperidineaceticacid monohydrochloride (as prepared in Example B.16.a) (0.000084 mol) inDCM (4 ml) and N,N-diisopropylethylamine (0.00010 mol) stirred undernitrogen at −20° C. and the mixture was stirred for 10 minutes.1-[Bis(dimethylamino)methylene]-tetrafluoroborate(1-)-1H-benzotriazolium3-oxide (TBTU) (0.00013 mol) was added and the reaction mixture wasstirred for 30 minutes at −20° C. The mixture was allowed to graduallywarm to room temperature and the reaction mixture was stirred for 75hours at room temperature. The reaction mixture was washed with water (1ml), then filtered through Extrelut™ and the filter residue was rinsedthree times with 3 ml of DCM. The filtrate was evaporated and theresidue was purified by HPLC (Waters column, with Xterra MS C18; eluent:[(0.5% NH₄OAc in H₂O)/CH₃CN 90/10)]/CH₃OH/CH₃CN (0 min) 75/25/0, (10min) 0/50/50, (16 min) 0/0/100, (18.10-20.00 min) 75/25/0). The productfractions were collected and the organic solvent was evaporated. Theaqueous concentrates were partitioned between DCM and an aqueous Na₂CO₃solution. The combined organic layers were separated, dried, filteredand the filtrate was blown dry under nitrogen at 50° C. The residue wasdried (vacuum, 60° C.), yielding compound (220).

EXAMPLE B.24

N,N-diisopropylethylamine (0.0010 mol) was added to a mixture ofα-phenyl-4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-1-piperidine-aceticacid monohydrochloride (as prepared in Example B.16.a) (0.000084 mol) inDCM (4 ml). Ethanol (0.00017 mol) and1-[bis(dimethylamino)methylene]-tetrafluoroborate(1-)-1H-benzotriazolium3-oxide (TBTU) (0.00013 mol) were added. The reaction mixture wasstirred for 75 hours at room temperature. Water (1 ml) was added. Themixture was stirred for 30 minutes, then filtered through Extrelut™,rinsed 3 times with DCM (3 ml each time) and the filtrate wasevaporated. The residue was dissolved in DCM, washed with 1 ml of 1 NHCl, filtered through Extrelut™ and the filtrate was washed with asaturated aqueous NaHCO₃ solution (1 ml). This mixture was filteredthrough Extrelut™. The filtrate was collected, and the filter residuewas washed with DCM (2×4 ml). The filtrate was evaporated. Each residuewas purified by HPLC (Waters column, with Xterra MS C18; eluent: [(0.5%NH₄OAc in H₂O)/CH₃CN 90/10)]/CH₃OH/CH₃CN (0 min) 75/25/0, (10 min)0/50/50, (16 min) 0/0/100, (18.10-20.00 min) 75/25/0). The productfractions were collected and the organic solvent was evaporated. Theaqueous concentrates were partitioned between DCM and an aqueous Na₂CO₃solution. The combined organic layers were separated, dried, filteredand the filtrate was blown dry under nitrogen at 50° C. The residue wasdried (vacuum, 60° C.), yielding compound (222).

EXAMPLE B.25

a) A mixture of compound (39) (0.0014 mol) in concentrated HCl (25 ml)and dioxane (20 ml) was stirred and refluxed for 4 hours, cooled andpoured out into water. The mixture was extracted with DCM. The organiclayer was separated, dried, filtered and the solvent was evaporated. Theresidue was triturated in DIPE. The precipitate was filtered off anddried, yielding 0.48 g ofα-phenyl-1-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl]amino]phenyl]-4-piperidineaceticacid (intermediate 26) (mp. 196° C.).

b) Ethylbromide (1.2 equivalent, 0.00010 mol) was added to a mixture ofintermediate (26) (0.000084 mol) in DMF (5 ml) and Cs₂CO₃ (0.00018 mol)and the reaction mixture was stirred for 3 hours at 70° C. The solventwas evaporated. The residue was partitioned between water and DCM. Theextract's solvent was evaporated. The residue was purified by HPLC(Waters column, with Xterra MS C18; eluent: [(0.5% NH₄OAc in H₂O)/CH₃CN90/10)]/CH₃CN (0 min) 85/15, (10 min) 10/90, (16 min) 0/100,(18.10-20.00 min) 85/15). The product fractions were collected and theorganic solvent was evaporated. The aqueous concentrates were extractedand the extract's solvent was evaporated, yielding compound (243).

EXAMPLE B.26

Acetyl chloride (0.0007 mol) was added to resin (XI) (0.00011 mol) inDCM (4 ml). N,N-dimethyl-4-pyridinamine (0.00011 mol) was added.N,N-diisopropyl-ethylamine (0.0011 mol) was added and the reactionmixture was shaken overnight at room temperature. The mixture wasfiltered and the filter residue was washed with DCM, methanol, DCM,methanol, CHDCM2Cl2, methanol, and DCM. TFA/TIS/CH₂Cl₂ (49/2/49) (4 ml)was added and the mixture was shaken for 2 hours at room temperature.The mixture was filtered, More TFA/TIS/CH₂Cl₂ (49/2/49) (2 ml) was addedand the mixture was shaken for 15 minutes, then filtered and the filterresidue was washed with DCM (2 ml). The filtrates were blown dry undernitrogen. The residue was purified by HPLC over Purospher Star RP-18 (20g, 5 μm; eluent: ((0.5% NH₄OAc in H₂O)/CH₃CN 90/10)/CH₃OH/CH₃CN (0 min)75/25/0, (10.00 min) 0/50/50, (16.00 min) 0/0/100, (18.10-20 min)75/25/0). The desired fractions were collected and the organic solventwas evaporated. The aqueous concentrate was extracted and the extract'ssolvent was evaporated, yielding 0.001 g of compound (253).

EXAMPLE B.27

Methanol (0.5 ml) was added to resin (XII) (0.0002 mol) in DCM (4 ml).N,N-dimethyl-4-pyridinamine (0.0002 mol) was added. DIPEA (0.002 mol)was added and the reaction mixture was shaken for 18 hours at roomtemperature. The mixture was filtered and the filter residue was washedwith DCM (3×), methanol (3×), DCM (3×), methanol (3×), DCM (3×),methanol (3×), DCM (3×). TFA/TIS/CH₂Cl₂ (49/2/49) (4 ml) was added andthe mixture was shaken for 2 hours at room temperature. The mixture wasfiltered, More TFA/TIS/CH₂Cl₂ (49/2/49) (2 ml) was added and the mixturewas shaken for 15 minutes, then filtered and the filter residue waswashed with DCM (2 ml). The filtrates were blown dry under nitrogen. Theresidue was purified by HPLC over Purospher Star RP-18 (20 g, 5 μm;eluent: ((0.5% NH₄OAc in H₂O)/CH₃CN 90/10)/CH₃OH/CH₃CN (0 min) 75/25/0,(10.00 min) 0/50/50, (16.00 min) 0/0/100, (18.10-20 min) 75/25/0). Thedesired fractions were collected and the organic solvent was evaporated.The aqueous concentrate was extracted and the extract's solvent wasevaporated, yielding 0.002 g of compound (251).

EXAMPLE B.28

A mixture of intermediate (31) (0.0006 mol), ethylamine hydrochloride(0.0015 mol), EDCl (0.0007 mol), HOBT (0.0007 mol) and triethylamine(0.0015 mol) in DCM (10 ml) was stirred at room temperature overnight.Water was added. The mixture was extracted with DCM. The organic layerwas separated, dried, filtered, and the solvent was evaporated. Theresidue was purified by column chromatography over kromasil (eluent:DCM). The pure fractions were collected and the solvent was evaporated,yielding 0.034 g of compound (276).

EXAMPLE B.29

A mixture of intermediate (29) (0.0045 mol), 3-thienyl boronic acid(0.036 mol), PdCl₂(PPh₃)₂ (0.0009 mol) and Na₂CO₃ (0.072 mol) in dioxane(50 ml) was stirred and refluxed for 30 minutes. Water was added. Themixture was extracted with ethyl acetate. The organic layer wasseparated, dried, filtered, and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent: DCM/ethylacetate 90/10). The pure fractions were collected and the solvent wasevaporated, yielding compound (267) (mp. 150° C.).

EXAMPLE B.30

A mixture of intermediate (29) (0.0025 mol), 3-pyridinyl boronic acid(0.02 mol), PdCl₂(PPh₃)₂ (0.005 mol) and Na₂CO₃ (0.04 mol) in dioxane(30 ml) was stirred and refluxed for 3 hours. Water was added. Themixture was extracted with ethyl acetate. The organic layer wasseparated, dried, filtered, and the solvent was evaporated. The residuewas purified by column chromatography over silica gel (eluent:CH₂Cl₂/CH₃OH/NH₄OH 97/3/0.1), yielding compound (270) (mp. 194° C.).

Table F-1 lists the polyarylcarboxamide compounds of the presentinvention, together with their detailed formulae, that were preparedaccording to one of the above examples B.1 to B.20. In this table, theabbreviation “.C₂HF₃O₂” stands for the trifluoroacetate salt, “.C₃H₈O”stands for the 2-propanolate salt, and “.CH₄O” stands for themethanolate salt of the said compound. TABLE F-1

C. PHARMACOLOGICAL EXAMPLES

C.1. Quantification of the Secretion of ApoB.

HepG2 cells were cultured in 24-well plates in Minimal Essential MediumRega 3 containing 10% fetal calf serum. Rega 3 has the followingcomposition: CaCl₂ (264 μg/ml), KCl (400 μg/ml), MgSO₄.7H₂O (200 μg/ml),NaCl (6800 μg/ml), NaHCO₃ (850 μg/ml), NaH₂PO₄.H₂O (158 μg/ml),D-glucose (1000 μg/ml), phenol red (10 μg/ml), L-alanine (8.9 μg/ml),L-arginine HCl (12 μg/ml), L-asparagine.H₂O (15 μg/ml), L-aspartic acid(13.3 μg/ml), L-cystine (24 μg/ml), L-glutamic acid (14.7 μg/ml),glycine (7.5 μg/ml), L-histidine.HCl.H₂O (42 μg/ml), L-isoleucine (52μg/ml), L-leucine (52 μg/ml), L-lysine.HCl (72.5 μg/ml), L-methionine(15 μg/ml), L-phenylalanine (32 μg/ml), L-proline (11.5 μg/ml), L-serine(10.5 μg/ml), L-threonine (48 μg/ml), L-tryptophan (10 μg/ml),L-tyrosine (36 μg/ml), L-valine (46 μg/ml), D-Ca pantothenate (1 μg/ml),choline chloride (1 μg/ml), folic acid (1 μg/ml), 1-enositol (2 μg/ml),nicotinamide (1 μg/ml), pyridoxal HCl (1 μg/ml), riboflavin (0.1 μg/ml)and thiamine HCl (1 μg/ml).

At 70% confluency, the medium was changed and the test compound orcarrier (dimethylsulfoxide, 0.4% final concentration) was added. After24 hours of incubation, the medium was transferred to Eppendorf tubesand cleared by centrifugation. A sheep antibody directed against eitherapo B was added to the supernatant and the mixture was kept at 8° C. for24 hours. Then, rabbit anti-sheep antibody was added and the immunecomplex was allowed to precipitate for 24 hours at 8° C. Theimmunoprecipitate was pelleted by centrifugation for 25 minutes at 1320g and washed twice with a buffer containing 40 mM4-morpholinepropanesulfonic acid, 40 mM NaH₂PO₄, 100 mM NaF, 0.2 mMdithiothreitol, 5 mM ethylenediamine tetraacetic acid, 5 mM ethylenebis(oxyethylenenitrilo) tetraacetic acid, 1% Triton-X-100, 0.5% sodiumdeoxycholate, 0.1% sodium dodecylsulphate, 0.2 μM leupeptin and 0.2 μMphenylmethylsulphonylfluoride. Radioactivity in the pellet wasquantified by liquid scintillation counting.

Resulting IC₅₀ values are enumerated in Table C.1 for a number ofcompounds No. 1 to No. 123. TABLE C.1 Co. No. pIC₅₀ 1 8.103 2 6.974 37.591 4 5.523 5 6.802 6 6.967 7 6.583 8 7.221 9 6.655 10 6.618 11 8.33512 6.636 13 7.523 14 5.523 15 6.688 16 7.077 17 6.702 18 6.687 19 6.57820 6.005 21 6.611 22 6.984 23 5.523 24 6.072 25 6.542 26 6.561 27 5.88528 6.115 29 5.523 30 6.782 31 5.894 32 5.621 33 5.523 34 5.809 35 5.52336 7.523 37 7.507 38 8.179 39 7.791 40 7.586 41 7.666 42 5.523 43 5.75144 5.981 45 5.523 46 6.336 47 6.702 48 6.198 49 6.627 50 7.028 51 7.16352 6.531 53 8.736 54 8.103 55 7.523 56 7.523 57 8.121 58 7.523 59 7.52360 7.523 61 8.414 62 7.19 63 6.912 64 6.799 65 6.62 66 7.099 67 6.608 687.523 69 8.051 70 7.523 71 7.987 72 7.523 73 8.216 74 7.523 75 7.943 767.286 77 7.523 78 7.488 79 7.301 80 6.448 81 6.749 82 7.011 83 7.364 847.1 85 6.888 86 7.075 87 8.688 88 7.523 89 6.44 90 7.851 91 8.061 927.199 93 7.141 94 7.356 95 7.523 96 7.493 97 6.63 98 7.237 99 7.523 998.062 100 7.935 101 6.684 102 7.732 103 7.133 104 8.1 105 7.043 106 6.6107 6.535 108 6.725 109 5.833 110 6.8 111 6.655 112 6.363 113 6.938 1146.078 115 5.766 116 6.414 117 6.916 118 6.895 119 6.757 120 6.447 1215.676 122 6.383 123 6.618 129 5.557 130 6.444 131 6.38 132 7.299 133<5.523 134 7.185 135 6.826 136 6.829 137 5.752 138 7.003 139 7.065 1407.693 141 7.601 142 6.944 143 6.631 144 6.695 145 6.732 146 6.467 1476.542 148 7.219 149 7.38 150 6.761 151 6.213 152 7.025 153 5.809 1545.634 156 6.915 157 6.97 158 7.671 159 6.973 160 7.489 161 7.162 1627.015 163 6.602 164 7 165 7.482 166 7.444 167 >7.523 168 6.881 174 7.035175 >7.523 176 6.873 177 6.583 178 7.465 179 6.395 180 6.945 181 8.48182 8.118 183 7.666 184 8.505 185 7.312 186 6.698 187 7.386 188 8 1896.979 190 8.193 191 8.143 192 6.802 193 6.629 194 7.367 195 7.047 1966.999 197 7.783 198 7.136 200 7.096 201 >7.523 202 6.736 203 8.333 2046.369 205 7.323 206 6.106 207 >7.523 208 8.126 209 8.099 210 6.316 2117.702 212 >7.523 213 >7.523 214 >7.523 215 >7.523 216 7.327 217 5.57218 >7.523 219 7.105 220 >7.523 221 >7.523 222 7.716 223 6.432 224 6.254225 7.17 227 6.727 229 7.409 230 8.31 231 >7.523 232 >7.523 233 >7.523234 >7.523 235 >7.523 236 7.663 237 >7.523 238 7.824 239 7.855 240 7.982241 7.578 242 8.133 243 >7.523 245 6.28 246 6.762 247 <5.523 248 7.164249 <5.523 250 6.632 251 8.016 252 7.915 253 6.887 254 7.541 255 8.298256 7.821 257 7.857 258 6.856 259 6.377 260 >7.523 261 6.129 262 6.253263 6.555 266 7.591C.2. MTP Assay

MTP activity was measured using an assay similar to one described by J.R. Wetterau and D. B. Zilversmit in Chemistry and Physics of Lipids(1985) 38, 205-22. In order to prepare the donor and acceptor vesicles,the appropriate lipids in chloroform were put into a glass test tube anddried under a stream of nitrogen. A buffer containing 15 mM Tris-HCl (pH7.5), 1 mM ethylenediamine tetra-acetic acid, 40 mM NaCl, 0.02% NaN₃(assay buffer) was added to the dried lipid. The mixture was vortexedbriefly and the lipids were then allowed to hydrate for 20 minutes onice. Vesicles were then prepared by bath sonication (using a Branson2200 device) at room temperature for at most 15 minutes. Butylatedhydroxytoluene was included in all vesicle preparations at aconcentration of 0.1%. The lipid transfer assay mixture contained donorvesicles (40 nmole phosphatidylcholine, 7.5 mole % cardiolipin and 0.25mole % glycerol tri [1-¹⁴C]-oleate), acceptor vesicles (240 nmolphosphatidylcholine) and 5 mg bovine serum albumin in a total volume of675 μl in a 1.5 ml microcentrifuge tube. Test compounds were addeddissolved in dimethylsulfoxide (0.13% final concentration). After 5minutes of pre-incubation at 37° C., the reaction was started by theaddition of MTP in 100 μl of a dialysis buffer. The reaction was stoppedby the addition of 400 μl diethylaminoalkyl (DEAE)-52 cellulose(Sephadex) pre-equilibrated in 15 mM Tris-HCl (pH 7.5), 1 mMethylenediamine tetra-acetic acid and 0.02% NaN₃ (1:1 volume/volume).The mixture was agitated for 4 minutes and centrifuged for 2 minutes atmaximum speed in an Eppendorf centrifuge (4° C.) to pellet theDEAE-52-bound donor vesicles. An aliquot of the supernatant containingthe acceptor liposomes was counted and the [¹⁴C]-counts were used tocalculate the percent triglyceride transfer from donor to acceptorvesicles.

Resulting IC₅₀ values are enumerated in Table C.2 for some of theabove-referred compounds. TABLE C.2 Co. No. pIC₅₀ 1 7.864 3 7.735 66.703 7 6.44 10 <5.523 11 8.136 16 6.682 39 7.922 40 8.344 41 8.063 548.269 55 8.37 57 8.163 58 7.799 60 8.082 61 8.32 62 7.98 75 8.077 878.495 199 8.334 203 8.682 222 8.075 229 7.279 230 8.439 232 7.602 2398.703 241 7.985 242 7.94 264 7.497 265 8.25

1-18. (canceled)
 19. A compound represented by the formula:

a stereochemically isomeric form thereof or a pharmaceuticallyacceptable addition salt thereof.
 20. The compound of claim 19, which isstereoisomerically pure.
 21. The compound of claim 19, which isenantiomerically pure.
 22. The compound of claim 19, which is the (+)enantiomer.
 23. The compound of claim 19, which is the (−) enantiomer.24. A pharmaceutical composition comprising at least onepharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound according to claim
 19. 25. A pharmaceuticalcomposition according to claim 24, further comprising at least oneadditional lipid-lowering agent.
 26. A method of treating hyperlipidemiacomprising administering to a patient suffering from hyperlipidemia atherapeutically effective amount of a compound of claim
 19. 27. A methodof treating obesity comprising administering to a patient suffering fromobesity a therapeutically effective amount of a compound of claim 19.28. A method of treating atherosclerosis comprising administering to apatient suffering from atherosclerosis a therapeutically effectiveamount of a compound of claim
 19. 28. A method of treating type IIdiabetes comprising administering to a patient suffering from type IIdiabetes a therapeutically effective amount of a compound of claim 19.29. A method of treating hypertriglyceridemia comprising administeringto a patient suffering from hypertriglyceridemia a therapeuticallyeffective amount of a compound of claim
 19. 30. A method of treating adisorder caused by an excess of very low density lipoproteins (VLDL) orlow density lipoproteins (LDL) comprising administering to a patientsuffering from such a disorder a therapeutically effective amount of acompound of claim 19.